UA120945C2 - Triazolopyrimidine compounds and uses thereof - Google Patents

Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be use-fill for treating a PRC2-mediated disease or disorder: wherein R1, R2, R3, R4, R5, and n are as defined herein.

Description

FIELD OF THE INVENTION

The present disclosure relates to triazolopyrimidine compounds, to compositions comprising such compounds, and to their use in the treatment of diseases or disorders mediated by Roiusotre repressive complex 2 (RES2).

TECHNICAL LEVEL

Regioproteins (Re) are chromatin-modifying enzymes dysregulated in many human cancers. RoiYusotr repressive complex 2 (RKS2), which includes

ZY212 (suppressor of 7le5ie 12), EEO (embryonic ectoderm development), and the catalytic subunit, E2H2 (enhancer of 7e5ie homolog 2), repress genes by methylating the core histone NZ lysine 27 (NZK27teZz) in and around the promoter regions of target genes. PKS2 is a critical component of the cellular machinery involved in the epigenetic regulation of gene transcription, and performs a critical function in tissue development and differentiation and regeneration. Despite the fact that E2H2 is the catalytic subunit, PES2 requires at least

EEO and 50212 for their methyltransferase activity EEO, 502212 and E/H2 are overexpressed in many cancers including but not limited to breast cancer, prostate cancer, hepatocellular carcinoma, etc. E2H2-activating mutations have been identified in patients with CI ALL. (diffuse large B-cell lymphoma) and patients with RI (follicular lymphoma). Inhibition of PES2 methyltransferase activity by compounds that compete with the cofactor 5-adenosyl methionine (ZAM) in OSI ALL reverses NZK27 methylation, reactivates target gene expression, and inhibits tumor growth. Ago

PKS2 represents a pharmacological target for I ALL. and other cancers. In particular, there is a need for small molecules that inhibit the activity of PES2. The present invention satisfies this need.

ESSENCE OF THE INVENTION

This disclosure relates to the compound of Formula (1): (be it xx

N in M M with re

M in va y;

Meme () in which E", B, VU, B", B? and n are as defined herein, including stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, or solvates thereof, which may be used to treat PKS2-mediated diseases or disorders.

The present disclosure also relates to methods and intermediates for the preparation of compounds according to the present disclosure.

The present disclosure also relates to pharmaceutical compositions comprising at least one of the compounds according to the present disclosure and at least one pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition may further include at least one additional therapeutic agent. Of particular interest are additional therapeutic agents selected from: other anticancer agents, immunomodulators, antiallergic agents, antinausea agents (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

Compounds of the present disclosure may be used in the treatment of diseases or disorders mediated by EEO and/or RES2.

The compounds of the present disclosure may be used in therapy.

The compounds of the present disclosure can be used for the preparation of a medicament for the treatment of diseases or disorders mediated by EEO and/or RES2.

The present disclosure relates to a method of treating diseases or disorders mediated by EEJU and/or PKC2, comprising administering to a patient a therapeutically effective amount of a first therapeutic agent, if needed with a second therapeutic agent, wherein the first therapeutic agent is a compound of the present disclosure, and the second therapeutic agent agent is one other type of therapeutic agent.

Examples of diseases or disorders mediated by EEO and/or PKC2 include, but are not limited to: diffuse large B-cell lymphoma (ALL), follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rod-shaped tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumors including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell cancer, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, such as rhabdomyosarcoma (KM5), Kaposi's sarcoma, synovial sarcoma, osteosarcoma, and Ewing's sarcoma.

The present disclosure relates to a method of treating diseases or disorders mediated by EEO and/or RES2, comprising administering to a patient a therapeutically effective amount of a first therapeutic agent, if needed with a second therapeutic agent, wherein the first therapeutic agent is an EEO inhibitor, and the second therapeutic agent is one another type of therapeutic agent; wherein the diseases or disorders are selected from diffuse large B-cell lymphoma (BCL), follicular lymphoma, other lymphomas, leukemia, multiple myeloma, gastric cancer, malignant rod-shaped tumor, and hepatocellular carcinoma.

The compounds according to this disclosure can be used individually, in combination with other compounds according to this disclosure, or in combination with one or more, preferably one or two other agents, simultaneously or sequentially.

Other features and advantages of the present disclosure will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION

I. COMPOUNDS

In the first aspect, this disclosure relates, ipieg aa, to the compound of Formula (1): (budo be!

Id. t M M r v- vo 7

Mom () or to its pharmaceutically acceptable salt, in which: sh--l denotes a single bond or a double bond;

IN! and 22 independently represent H or halogen;

Zo BZ is independently selected from: halogen, phenyl and 5-6-membered heteroaryl, which includes carbon atoms and 1-4 heteroatoms selected from M, MKea, O and 5(O)p; and the indicated phenyl and heteroaryl are substituted by 0-3 VZA; each KZA is independently selected from: halogen, CM, -(O)t-(C1-C7 alkyl, substituted 0-1 VZV), C4-

Ce haloalkyl, Ci-Ce haloalkoxy, B3E, -ONZE, -0(-0)839, MAE, -C(-O)MAZEVZE, - z5 0 МНО(-0)В8о, -5(-0)2839, - 5(-0)2MVZEVZE, -"MNO(-0)2(C1-Cya alkyl) and -SVZSZEDZO:

VZV is independently selected from: OH, MV, C1-Cα alkoxy, -C(-O)MVeV, -5(-0)2(C1-Cα alkyl), -

МНОТ(-о0)(С1-Са alkyl) and 5-6-membered heterocycloalkyl, which includes carbon atoms and 1-2 heteroatoms selected from M, MAKe, O and 5(О)p; and the indicated heterocycloalkyl is substituted by 0-2

Ve; each KZ is independently selected from: C3-C6 cycloalkyl, phenyl and a 4-7 membered heterocycle including carbon atoms and 1-4 heteroatoms selected from M, MKe, O and 5(O)p; and each group is replaced by 0-2 No; each ZO independently selected from: C-C4 alkyl and KZS;

VE and 232 are, in each case, independently selected from: H and C1-C6 alkyl; each EZE is independently selected from: H and Si-Slalkyl substituted with 0-1 Be;

B" is independently selected from: H, halogen and C-C" alkyl;

IN? independently selected from OH and C:-Cx alkyl; each Pg is independently selected from: H, -0, C-C alkyl substituted by 0-1 Be, -C(-0O)H, -C(-0)(C1-

Cl alkyl), -CO2(C1-Ca alkyl), C3-Cv cycloalkyl and benzyl;

BO V? independently selected from: halogen, OH, and C1-Cα alkoxy;

each K- is independently selected from: 5-0, halogen, OH, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkyl;

VZ is independently selected from: ОН and МЕ;

Bc and P", in each case, are independently selected from: H and C1-C6 alkyl; each p is independently selected from 0, 1 and 2; and m and n, in each case, are independently selected from 0 and 1.

In another aspect, this disclosure relates to a compound of Formula (IA): (vunito . n

Kk M M what's up

M Vk v u; or to a pharmaceutically acceptable salt thereof, within the scope of the first aspect; in which:

B' and B? independently denote H or halogen;

BZ is independently selected from: halogen, phenyl and 5-6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from M, MKe, O and 5(O)p; and the indicated phenyl and heteroaryl are substituted by 0-3 VZA; each KZA is independently selected from: halogen, CM, -(O)t-(C1-C6 alkyl substituted 0-1 VZV), C-

St haloalkyl, Ci-Ce haloalkoxy, KZ3C, -ONZE, -0(-0)830, MAZEDVZE, -С(-0О)MAZEVZE, -

МНО(-О)ВЗо, -5(-0)28309, -5(-0)2МВЗЕВЗЕ, -"МНАО(-0)2(С1-Са alkyl) and -"СВЗОДЗЕДЗО;

VZV is independently selected from: OH, MAV, С1-Са4 alkoxy, -С(-О)МАеВ, -5(-0)2(С1-Са alkyl), -

МНОТ(-0)(С1-Са alkyl) and 5-6-membered heterocycloalkyl, which includes carbon atoms and 1-2 heteroatoms selected from M, MAKag, O and 5(O)p; and the indicated heterocycloalkyl is substituted by 0-2 ve; each KZ is independently selected from: C3-C6 cycloalkyl, phenyl, and a 4-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from M, MKe, O, and 5(O)p; and each group is replaced by 0-2 No; each ZO independently selected from: C1-Cα alkyl and VZS;

ZE and Bc are, in each case, independently selected from: H and C1-C6 alkyl; each EZE is independently selected from: H and Si-Slalkyl substituted with 0-1 Be;

IN? independently selected from: H, halogen, and Si-Slalkyl;

AZ independently denotes Ci-Cl alkyl; each B2 is independently selected from: H, -0, C1-Ca alkyl, substituted 0-1 Be, -С(-О)Н, -Ф(-0)(С:-

Slalkyl), -CO4(C1-Slalkyl), C3-Ce cycloalkyl and benzyl;

IN? independently selected from: halogen, OH and Ci-C" alkoxy; each K- is independently selected from: 5-0, halogen, OH, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkyl;

VZ is independently selected from: ОН and МЕ;

Bc and P", in each case, are independently selected from: H and C1-C6 alkyl; each p is independently selected from 0, 1 and 2; and m and n, in each case, are independently selected from 0 and 1.

In a second aspect, this disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within the scope of the first aspect; in which: each KZA is independently selected from: halogen, CM, -(O)t-(C1-Ca alkyl substituted 0-1 VZV), C-

Ca haloalkyl, C-C4 haloalkoxy, Ks, -0(-0)830, MAZEVZE, -0(-0O)MAZEVZE, -5(-0)2890, - yam c i -C" alkyl) 5(-O) 2MNASE, -MNU(-0)2(C1-Ca alkyl), -O-C3-Ce cycloalkyl and ;

Ba is independently selected from: Н, -0, C:1-Са alkyl, substituted 0-1 Бе, -С(-О)Н, -Ф(-0)(С1-С4 alkyl), -СО5(С1-Са alkyl) and C3-C8 cycloalkyl;

B" denotes H;

t is independently selected from 0 and 1; and n-0.

In a third aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within the scope of the first or second aspect; in which:

B' independently denotes H or E;

B2 denotes H; and

BZ is independently selected from: phenyl and b-membered heteroaryl, including carbon atoms and 1-2 heteroatoms selected from M and MK2g; and the specified phenyl and heteroaryl is substituted 0-3

VA,

In a fourth aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first, second and third aspects; in which:

BZ is independently selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl; and each group is replaced by 0-3 VZA.

In a fifth aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first to fourth aspects, wherein: A. shchi

Shh their she What their how m zd

VZ is independently selected from: (Vo, (KT and (Ko,

In a sixth aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first to fifth aspects, wherein:

PROS and CONS:

BZ is independently selected from: "c, (ke a, Ko and (E, each KZA independently selected from: halogen, CM, -(O)t-(C1-Ca alkyl substituted 0-1 VZB), C-

C. haloalkyl, C-C4 haloalkoxy, -C(-O)MH», -C(-0O)MH(Ci-Ca alkyl), -C(-0O)M(C1-Ca4 alkyl)», -C( -О)М(С1-Са4 alkylCHn)2М(С1-Са alkyl)г,, -СНаМНО(-О0)(С1-Са alkyl), -5(-0)2890, -

З(-0)2МН(С1-Са alkyl, substituted 0-1 OH), -МНО(-О)2(С1-Са alkyl), МН», -МН(С1-Са alkyl), -

M(C1-Cα alkyl)2, C3-C6 cycloalkyl,

Kk mA Ca alkyt)oz 5 "M

M (OH vn g " -- t Y r y -

MA , : -ef , that, (bossa alkyl)o-z their shi sho

Y. lm lm ; M M. -0 and chl t pl

Sat tyu what te dra , ra | ra lm lm

Mom home " ik M

M | So, alkyl)oo M

Y y x t, o uOSYata v

VZV is independently selected from: OH, МН», МН(Си-Са alkyl), M(С1-Са alkyl)г, Си-С4 alkoxy, -

M. M b, S y y he! o halogenium iv ia

C(-O)M(C1-Cya alkyl)", -5(-0)2(C1-C1 alkyl), t, K and Kk;

Bzo is independently selected from: C1-C: alkyl and 1H-piperidin-4-yl; and each Kg is independently selected from: H, C1-C6 alkyl, -C(-0O)H, -C(-0)(C1-C6 alkyl) and -005(C1-C4 alkyl).

In a seventh aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first to sixth aspects, wherein:

M/o I Z p

Sk x (IVF those ZA "z

BZ is independently selected from: (Kue ha (bló ; each KZA is independently selected from: halogen, CM, -(O)t-(C1-Ca alkyl, substituted 0-1 BB), C.-

C. haloalkyl, C-C4 haloalkoxy, -C(-O)MH», -C(-0O)MH(Ci-Ca alkyl), -C(-0O)M(C1-Ca4 alkyl)», -C( -0О)М(С1-Са alkylСНег)2М(С1-Са alkyl)», -СНаМНО(-О0)(С1-Са alkyl), -5(-0)2(С01-Са4 "non alkyl), MHg, MH(Ci-C4 alkyl), M(Ci-C4 alkyl)", C3-Ce cycloalkyl, , o o lam

MS sa alkyl-z b, "Z b a

AND)

Z Ko M hoya alkyl |: y yayamooyarm li. also M M (in M. lm y t sh: "in So E Y S some)

With her and

So in: і: і і ne lu chyra m

With in 87 and that

VZV is independently selected from: OH, M(C1-Cα alkyl)g, C-C4 alkoxy, -C(-0O)M(C1-Cα alkyl)g, - direct lm

M M

U, S and

Xh (halogen)oo ia

C(-0)2(C1-C1 alkyl), Cho a and C and each Kg independently selected from: H, C1-C1 alkyl, -C(-0O)H, -C(-0)(C1-C1 alkyl) ) and -005(C1-C4 alkyl).

In an eighth aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first to seventh aspects, wherein: each ZA is independently selected from: P, Cl, CH3, - "SN"ON, SNR, SNE", SEz, SM, -OSN", -

ОСН»СНИ, -ОСН(СНзг)», -ОСНЕ», -С(-0О)М(СНзг)», -СНаМНО(-О)СНа, -5(-0)2СНз, МН»

«ia mai shk, C C cyclopropyl, - LO and 8.

In the ninth aspect, this disclosure relates to a compound of Formula (IA-1):

M v i: u; and y -M y (IA-1) or to its pharmaceutically acceptable salt, within any of the aspects described above; in which:

AND! independently denotes H or E; and

VZA is independently selected from: PE, CH3, -CH2OH, CH», SNE», SEz and -OSN».

In a tenth aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within the first or second aspect; in which:

B' independently denotes H or E;

B2 denotes H;

BZ independently denotes a 5-membered heteroaryl, which includes carbon atoms and 1-4 heteroatoms selected from M, MA", O and 5(O)p; and the specified heteroaryl is substituted by 0-3 VZA; and

Be is independently selected from: H, C1-C" alkyl substituted with 0-1 Be, -C(-0O)H, -C(-0)(C1-Ca alkyl), -

CO5(C:-Cx alkyl), C3-Cv cycloalkyl and benzyl.

In an eleventh aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first, second and tenth aspects; in which:

No

Pow MMA o, where 5 |» ba TAN

M. M y; g re

VZ is independently selected from: , a , M , o lm (ZA

DIAMOND

What and V.

In another aspect, the present disclosure includes a compound of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof, within any of the first, second and tenth aspects; in which: min

In ZA

In (va and them.

YAM st ach e dl 5 Mo 0 MA

M g and g u; x M...;

VZ is independently selected from: where , o and 5 .

In a twelfth aspect, the present disclosure includes a compound of Formula (I) (IA) or (IA-1), or a pharmaceutically acceptable salt thereof, within any of the aspects described above, wherein:

B" denotes R.

In a thirteenth aspect, the present disclosure relates to a compound selected from those illustrated

From examples, or to a pharmaceutically acceptable salt thereof, including all compounds from Examples 1-245.

In a fourteenth aspect, the present disclosure relates to a compound selected from:

and E

M. MN m. M (

My (in; | in o ee M -x M

X hi | and

MM M-M M M-M

E and N

N. M. M

My o | 5 (6) - rliaa M

M M

Zh M U; and In M-m railway station M-M

M from z

E. e N

M M

M M | with (in; t R M M

Ha M | I;

IN; 2 t-m o ta, or its pharmaceutically acceptable salt.

In another embodiment, the invention relates to the compound of Example 1 or its pharmaceutically acceptable salt, and the compound is 8-(1,3-dimethyl-1H-pyrazol-5-yl)-

M-(5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-(1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine.

In another embodiment, the invention relates to the compound of Example 1, and the compound is /8-(1,3-dimethyl-1H-pyrazol-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4- ilumethyl)-

P1,2,4)griazoloi|4,3-s|Ipyrimidine-5-amine.

In another embodiment, the invention relates to the compound of Example 2 or its pharmaceutically acceptable salt, and the compound is /N-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3- yl)-(1,2,4Altriazolo|4,3-c|Ipyrimidin-5-amine.

In another embodiment, the invention relates to the compound of Example 2, and the compound is M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-8-(2-methylpyridin-3-yl)-

P1,2,4)griazoloi|4,3-s|Ipyrimidine-5-amine.

In another embodiment, the invention relates to the compound of Example 5 or its pharmaceutically acceptable salt, and the compound is /N-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-4- methylpyridin-3-yl)-1,2,4A|griazoly|4,3-s|Ipyrimidin-5-amine.

In another embodiment, the invention relates to the compound of Example 5, and the compound is M-(5-fluoro-2,3-dihydrobenzofuran-4-ylylmethyl)-8-(b-methoxy-4-methylpyridin-3-yl)-

P1,2,4)griazoloi|4,3-s|Ipyrimidine-5-amine.

In another embodiment, the invention relates to the compound of Example 8 or to its pharmaceutically acceptable salt, and the compound is 8-(2-cyclopropyl-4-methylpyrimidin-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran- 4-yl)umethyl)-I(1,2,ATgriazolo|4,3- c|Ipyrimidin-5-amine.

In another embodiment, the invention relates to the compound of Example 8, and the compound is //8-(2-cyclopropyl-4-methylpyrimidin-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-

Zoyl)umethyl)-P1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine.

In another embodiment, the invention relates to the compound of Example 207 or to its pharmaceutically acceptable salt, and the compound is M-(5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-(1, 2,4|triazolo|4,3-c|Ipyrimidine-5-amine.

In another embodiment, the invention relates to the compound of Example 207, and the compound is M-(5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-

P1,2,4)griazoloi|4,3-s|Ipyrimidine-5-amine.

In another embodiment, the invention relates to the compound of Example 233 or to its pharmaceutically acceptable salt, and the compound is /-M-(5-fluoro-2,3-

dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-1,2,4|griazolo|4,3-c|Ipyrimidin-5-amine.

In another embodiment, the invention relates to the compound of Example 233, and the compound is M-(5-fluoro-2,3-dihydrobenzofuran-4-ylmethyl)-8-(4-methyl-1H-imidazol-1-yl)-1 ,2,4)griazolo|4,3-s|Ipyrimidine-5-amine.

In another aspect, the present disclosure relates to a compound, or a pharmaceutically acceptable salt thereof, selected from any subpopulation of compounds within the thirteenth aspect.

In another embodiment, the invention relates to a compound or a pharmaceutically acceptable salt thereof, within any of the aspects from the first to the seventh aspect, in which:

VZ independently denotes 7 and each KZA is independently selected from: C-C4 alkyl, C-C4 alkoxy, C-C4 haloalkyl, -

COM(C1-C6 alkyl)", -5(-0)2(C1-C6 alkyl) and C3-C6 cycloalkyl.

In another embodiment, the invention relates to a compound or a pharmaceutically acceptable salt thereof, within any of the first to seventh aspects, in which:

Here you are

BZ independently denotes and each BZA is independently selected from: CH3, OSH3, -COM(CH3)»2, -51-0)4(CH33) and cyclopropyl.

In another embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt thereof, within any of the first to seventh aspects, wherein:

A r (Vu and St

VZ independently denotes I from: and each BZA is independently selected from: Ci-C4-Alkoxy, Ci-C. haloalkoxy and -O-C3-Cv cycloalkyl.

In another embodiment, the invention relates to a compound or a pharmaceutically acceptable salt thereof, within any of the aspects from the first to the seventh aspect, in which: uva . schi ra re

VZ independently denotes (Cl OH. and each VZA is independently selected from: OSN3, OSNoCHv»z, -"OSNE" and -O-cyclopropyl.

In another embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt thereof, within any of the first to seventh aspects, wherein:

SS vu o

VZ independently denotes and ;ta

Each BZA is independently selected from: C: and C4. Alkoxy, Ci-C.-halogenalkoxy and -O-C3-Cv cycloalkyl.

In another embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt thereof, within any of the first to sixth aspects, wherein:

we

WITH

Meuzdh

BZ independently denotes (o : and each KZA is independently selected from: halogen, CM, C-C4 alkyl, C-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkyl, M(C1-C6 alkyl)" and C3-Cv cycloalkyl .

In another embodiment, the invention relates to a compound, or a pharmaceutically acceptable salt thereof, within any of the first to sixth aspects, wherein:

Ж dz (by. independently denotes ; each KZA is independently selected from: halogen, CM, -(O)t-(С1-Са alkyl, substituted 0-1 BB), С.-

C. haloalkyl, C-C4 haloalkoxy, C(-O)MH», -5(-0)283s, -5(-0)2MH(Ci-Ca alkyl substituted by 0-1 OH), -MHO(- О)2(С1-Са alkyl), pie ry aa

And | school o m

M cho -b» ankil) Z 7 or torso ayakil ; and and WE.

VZV is independently selected from: OH, MNeg, M(C1-Ca alkyl)2 and -5(-0)2(C1-Ca alkyl); and

Bzs is independently selected from: C1-C6 alkyl and 1H-piperidin-4-yl.

In another aspect, the present disclosure includes a compound of Formula (IA) or a pharmaceutically acceptable salt thereof, within any of the first, second, tenth and eleventh aspects; in which: their

Guti" dm

We are Huta and S

VZ is independently selected from: la and TO.

In another aspect, the present disclosure includes a compound of Formula (IA) or a pharmaceutically acceptable salt thereof, within any of the first, second, tenth and eleventh aspects; in which: x halo"

AND

M.M for

VZ independently denotes Mk; each BZA is independently selected from: C1-C4 alkyl, C--C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkyl;

Vag is independently selected from: H, C1i-C alkyl, substituted 0-1 Kb, and C3-C6 cycloalkyl; and

IN? independently selected from: OH and C:-Ca alkoxy.

In another embodiment of the compounds according to the present disclosure, the value of ISvos5 MKM, using the binding tests of EEO AIrpazsgeep, I CM5 and/or EGI5A, disclosed herein, preferably, ISvos-1 μM, more preferably, ISvo-0.5 μM , even more preferably,

ICzox 0.1 µM.

I. OTHER EXECUTION OPTIONS

In another embodiment, this disclosure relates to a composition that includes at least one of the compounds in accordance with this disclosure or a pharmaceutically acceptable salt thereof.

In another embodiment, this disclosure relates to a pharmaceutical composition that includes at least one of the compounds in accordance with this disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

In another embodiment, this disclosure relates to a pharmaceutical composition that includes a therapeutically effective amount of at least one of the compounds in accordance with this disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical composition can be used in the treatment of diseases or disorders mediated by EEO and/or RES2.

In another embodiment, the present disclosure relates to a pharmaceutical composition as defined above, which additionally includes an additional therapeutic agent).

In another embodiment, this disclosure relates to a method of preparing a compound in accordance with this disclosure.

In another embodiment, the present disclosure relates to an intermediate compound for the preparation of a compound according to the present disclosure.

In another embodiment, this disclosure relates to a compound according to this disclosure for use in therapy, individually or, if necessary, in combination with another compound according to this disclosure and/or at least one other type of therapeutic agent.

In another embodiment, the present disclosure relates to a compound in accordance with the present disclosure for use in therapy for the treatment of diseases or disorders mediated by EEO and/or RCS, individually or, if necessary, in combination with another compound in accordance with the present disclosure and /"or at least one other type of therapeutic agent.

In another embodiment, the present disclosure relates to a method of treating diseases or disorders mediated by EEO and/or PKC2, comprising administering to a patient a therapeutically effective amount of at least one of the compounds according to the present disclosure, individually or, if necessary, in combination with another a compound in accordance with this disclosure and/or at least one other type of therapeutic agent.

In another embodiment, the present disclosure relates to a method of treating diseases or disorders mediated by EEO and/or PKC2, comprising administering to a patient a therapeutically effective amount of a first and a second therapeutic agent, wherein the first therapeutic agent is a compound according to the present disclosure, and the second therapeutic agent is another type of therapeutic agent.

In another embodiment, the present disclosure also relates to the use of a compound according to the present disclosure for the preparation of a medicament for the treatment of diseases or disorders mediated by EEO and/or RCS, individually or, if necessary, in combination with another compound according to this disclosure and/or at least one other type of therapeutic agent.

In another embodiment, the present disclosure relates to a combination preparation of a compound according to the present disclosure and an additional therapeutic agent(s) for use in therapy.

In another embodiment, the present disclosure relates to a combination of a compound according to the present disclosure and an additional therapeutic agent(s) for simultaneous or separate use in therapy.

In another embodiment, the present disclosure relates to a combination preparation of a compound according to the present disclosure and an additional therapeutic agent(s) for simultaneous, separate, or sequential use in the treatment of diseases or disorders mediated by EEJU and/or PKC2. The compound may be administered in the form of a pharmaceutical composition disclosed herein.

Examples of diseases or disorders mediated by EEO and/or RES2 include, but are not limited to, diffuse large B-cell lymphoma (CL ALL), follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rod-shaped tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer , head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors, and soft tissue sarcomas selected from rhabdomyosarcoma (KM5 ), Kaposi's sarcoma, synovial sarcoma, osteosarcoma, and Ewing's sarcoma.

In another embodiment, the present disclosure relates to a method of treating diseases or disorders mediated by EEO and/or PKC2, comprising administering to a patient a therapeutically effective amount of the first, if necessary, with a second therapeutic agent, wherein the first therapeutic agent is an EEO inhibitor, and the second therapeutic agent is one other type of therapeutic agent; wherein the diseases or disorders are selected from diffuse large B-cell lymphoma (0 ALL), follicular lymphoma, other lymphomas, leukemia, multiple myeloma, gastric cancer, malignant rod-shaped tumor, and hepatocellular carcinoma.

In another embodiment, the additional therapeutic agent(s) used in the combined pharmaceutical compositions or combined methods or combined use is selected from one or more, preferably from one to three, of the following therapeutic agents: other anticancer agents, immunomodulators, antiallergic agents, agents anti-nausea (or anti-emetic agents), analgesic agents, cytoprotective agents and combinations thereof.

Various (enumerated) disclosure options are described here. It is clear that the features defined in each embodiment may be combined with other specified features to provide other embodiments of this disclosure. It is also understood that each individual element of the embodiments is its own independent embodiment.

Other features of the present disclosure should become apparent from the foregoing descriptions of exemplary embodiments, which are provided to illustrate the disclosure and are not intended to limit it.

I. Definition

The general terms used above and below preferably have the following meanings in the context of this disclosure, unless otherwise indicated, and the more general terms wherever they are used, independently of each other, may be replaced by more specific definitions or may remain, as follows defining more specific embodiments of the invention.

All of the methods described herein may be performed in any suitable order, unless otherwise specified or otherwise clearly inconsistent with the context. The use of any and all examples or example language (eg, "such as") herein is intended merely to better illustrate the invention and is not intended to limit the claimed scope of the invention.

Terms used in the context of this disclosure (especially in the context of the claims) in the singular shall be construed to include both the singular and the plural, unless otherwise indicated or unless the context clearly dictates otherwise.

Within the scope of the invention, the term "heteroatoms" refers to atoms of nitrogen (M), oxygen (C) or sulfur (5), in particular, nitrogen or oxygen.

Unless otherwise stated, any heteroatom with unfilled valences is assumed to have hydrogen atoms sufficient to fill the valences.

Within the scope of the invention, the terms "alkyl" refer to the hydrocarbon radical of the general formula SMNgapa. An alkane radical can be straight or branched. for example, the term "C1-C10 alkyl" refers to a monovalent straight or branched aliphatic group containing from 1 to 10 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, heptyl, etc.).

The term "alkylene" refers to a divalent alkyl group. for example, the term "C1-Cv alkylene" refers to a divalent straight or branched aliphatic group containing from 1 to b carbon atoms (for example, methylene (-СНег-), ethylene (-СН»СНе-), n-propylene (-

CH.СНеСНег-), isopropylene (-СН(СН3)СНе»-), n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, etc.).

The term "Alkoxy" refers to alkyl bonded to oxygen, which may also be represented as -O-K or -OK, where K represents an alkyl group. "C 1 -C 6 alkoxy" or includes C 1 , C 2 , C 3 , C 1 , C 5 , and C 1 -C 6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy) and tert-butoxy. Similarly, "alkylthio" or "thiosalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached via a sulfur bridge; for example, methyl-5- and ethyl-5-. "Halogen" can be fluorine, chlorine, bromine, or iodine (preferred halogen substituents are fluorine and chlorine). "Haloalkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms substituted by one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which includes both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of 60 carbon atoms substituted with one or more fluorine atoms.

"Haloalkyl" is a haloalkyl group, as defined above, with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C1-C6 haloalkoxy" includes C1, C2, C3, Ca, Cx, and C6 haloalkyl groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Likewise, "haloalkylthio" or "thiohaloalkyloxy" is a haloalkyl group as defined above with the indicated number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-5- and pentafluoroethyl-5-.

The term "oxo" or -C(0)- refers to a carbonyl group, such as a ketone, aldehyde or part of an acid, ester, amide, lactone or lactam group.

The term "cycloalkyl" refers to a non-aromatic carbocyclic ring that is a fully hydrogenated ring, including mono-, bi-, or polycyclic ring systems. "C3-C6 cycloalkyl" includes C3, C4, C5, C5, C7 and C5 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.

The term "aryl" refers to 6-10-membered aromatic carbocyclic groups having a single ring (eg, phenyl) or fused ring systems (eg, naphthalene).

A typical aryl group is a phenyl group.

The term "benzyl", within the scope of the invention, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group. "Heterocycloalkyl" means cycloalkyl as defined in this application, provided that one or more ring carbon atoms are replaced by a group selected from O, M-, MK, C(O), 5, 5(O), and 5(O) ", and LC denotes hydrogen, C:alkyl, or a protecting group for nitrogen (for example, carbobenzyloxy, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4- dimethoxybenzyl, etc.). for example, 3-8 membered heterocycloalkyl includes epoxy, aziridinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, oxazolidinyl, thiazolidinyl, pyrrolidinyl, pyrrolidinyl-2-one, morpholino, piperazinyl, piperidinyl, piperidinyl, pyrazolidinyl , hexahydropyrimidinyl, 1,4-dioxa-8-aza-spiroI(4,5|dec-v-yl, thiomorpholino, sulfanomorphoylino, sulfonomorpholino, octahydropyrrolo|3,2-B|pyrrolyl, etc.

The term "partially saturated heterocycle" refers to a non-aromatic ring which

Zo is partially hydrogenated and can exist as a single ring, a bicyclic ring (including fused rings). Unless otherwise indicated, said heterocyclic ring is usually a 5- to 10-membered ring containing from 1 to 3 heteroatoms selected from O, M-, ME and 5 (preferably 1 or 2 heteroatoms). Partially saturated heterocyclic rings include such groups as dihydrofuranyl, dihydrooxazolyl, dihydropyridinyl, imidazolinyl, 1H-dihydroimidazolyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, etc. A partially saturated heterocyclic ring also includes groups in which the heterocyclic ring is fused to an aryl or heteroaryl ring (eg, 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1 .

The term "partially or fully saturated heterocycle" refers to a non-aromatic ring that is partially or fully hydrogenated and may exist as a single ring, a bicyclic ring (including fused rings), or a helical ring. Unless otherwise indicated, the heterocyclic ring is usually a 3-12 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. When the term "partially or fully saturated heterocycle" is used, it includes "heterocycloalkyl" and "partially saturated heterocycle". Examples of helical rings include 2,6-diazaspiro|3,4|heptanyl, 3-azaspiro|5,5)undecanyl, 3,9-diazaspiro|5,5)undecanyl, and the like.

The term "heteroaryl" refers to aromatic groups containing at least one heteroatom (eg, oxygen, sulfur, nitrogen, or combinations thereof) in a 5- to 10-membered aromatic ring system (eg, pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyrimidinyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, 1H-benzo|4)MC1,2, 3|Igriazolil, etc.).

A heteroaromatic group can consist of a single ring or a fused ring system.

A typical single heteroaryl ring is a 5- to 6-membered ring containing from one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen, and a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing from one up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen. A fused heteroaryl ring system can consist of two heteroaryl rings fused together, or a heteroaryl fused to an aryl (eg, phenyl).

When the term "heterocycle" is used, it includes "heterocycloalkyl", "partially or fully saturated heterocycle", "partially saturated heterocycle", "fully saturated heterocycle" and "heteroaryl".

The term "counterion" is used to refer to a negatively charged moiety such as chloride, bromide, hydroxide, acetate, and sulfate, or a positively charged moiety such as sodium (Mat), potassium (Kj), ammonium (CoMNH, where n-:0- 4, t--0-4 and tzhp-4) etc.

When a dotted ring is used in a ring structure, it indicates that the ring structure may be saturated, partially saturated, or unsaturated.

As mentioned herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valences are maintained and that the substitution results in a stable compound. When the substituent is a keto substituent (ie, 0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic groups. When a ring system (eg, carbocyclic or heterocyclic) is said to be substituted by a carbonyl group or double bond, it means that the carbonyl group or double bond is part of (i.e., is part of) the ring. Ring double bonds, within the scope of the invention, are double bonds created between two adjacent ring atoms (for example, C-C,

SAM or MAM).

Where nitrogen atoms (e.g., amines) exist in the compounds of the present disclosure, they can be converted to M-oxides by treatment with an oxidizing agent (e.g., teCRBA and/or hydrogen peroxide) to yield other compounds of the present disclosure. Thus, the nitrogen atoms shown and claimed are considered to cover both the nitrogen shown and its M-oxide (M(O)) derivative.

When any variable occurs more than once in any ingredient or formula of a compound, its definition in each case is independent of its definition in any other case. Thus, for example, if a group is shown to be substituted with 0-3 K groups, then said group may be unsubstituted or substituted with up to three K groups, and in each case K is chosen independently of the definition of K. For example, with respect to the first aspect, this refers to 0-3 BZA in the definition of EZ, such that when EZ is phenyl or b-membered heteroaryl, these groups are either unsubstituted (unsubstituted by C") or substituted by one, two

With or three EA groups, independently selected in each case from the given definitions for VA.

This also applies to the definitions for 0-2 VS in the definitions of EZV and EZS, and to 0-1 VU in the definition of KE,

When a bond with a substituent is shown to cross a bond connecting two atoms in a ring, then such a substituent can be attached to any atom in the ring. When a substituent is listed without specifying the atom on which such substituent is attached to another part of a compound of this formula, then such substituent may be attached through any atom in such substituent.

Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

As will be clear to a person skilled in the art, for example, a ketone (-CH-C-O) group in a molecule can tautomerize into its enol form (-C-C-OH). In this way, this disclosure covers all possible tautomers, even when the structure depicts only one of them.

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible, chemically and/or toxicologically, with the other ingredients included in the composition and/or with the mammal receiving treatment using them.

Unless otherwise indicated, the term "compounds of the present invention" or "compounds of the present disclosure" refers to compounds of Formula (I), (IA) or (IA-1) as well as to isomers such as stereoisomers (including diastereoisomers , enantiomers and racemates), geometric isomers, conformational isomers (including rotamers and astropisomers), tautomers, isotopically labeled compounds (including deuterium substitution), and internally formed groups (eg, polymorphs, solvates and/or hydrates). When a salt-forming group is present, then salts are also included, particularly pharmaceutically acceptable salts.

One skilled in the art will appreciate that the compounds of this disclosure may contain chiral centers and as such may exist in various isomeric forms. Within the scope of the invention, the term "isomers" refers to different compounds having the same molecular formula, but differing in structure and configuration of atoms. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. 111 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to denote a racemic mixture where appropriate. When specifying 60 stereochemistry for compounds of the present invention, a single stereoisomer with a known relative and absolute configuration of two chiral centers is determined using the standard K5 system (eg, (15, 25)); a single stereoisomer with known relative configuration but unknown absolute configuration is identified with asterisks (for example, (1К7,2КУ)); and a two-letter racemate (eg, (185, 285) as a racemic mixture of (1K, 2E) and (15, 25); (185, 25K) as a racemic mixture of (1E, 25) and (15, 2K)). "Diastereoisomers" are stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is determined according to the Kahn-Ingold-Prelog K-5 system.

When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as Я or 5. Separated compounds whose absolute configuration is unknown can be specified as (w) or (-)y depending on the direction (dextrorotatory or levorotatory) in which they rotate the plane of polarized light at the wavelength of the U-line of sodium. Separated compounds can also be determined by the respective retention times for the respective enantiomers/diastereomers using chiral HPLC.

Some of the compounds described herein contain one or more centers or axes of asymmetry and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, from the point of view of absolute stereochemistry, as (K)- or (5) -.

Geometric isomers can occur when a compound contains a double bond or some other feature that gives the molecule some structural stability. If the compound contains a double bond, the substituent can have an E or 7 configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

Conformational isomers (or conformers) are isomers that can differ in rotations about one or more bonds. Rotamers are conformers that differ in rotation around only one bond.

The term "atropisomer" refers to a structural isomer based on axial or planar chirality, which results from restricted rotation in the molecule.

Unless otherwise indicated, the compounds of this disclosure include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (B)- and (5)-isomers can be obtained using chiral synthons or chiral reagents or separated using standard methods (for example, separated on chiral chromatographic columns 5ES or HPLC, such as SNIVAI RAKF and SNIVAI! SEI F, available from SAISEI Sogr. using a suitable solvent or mixture of solvents to achieve good separation).

Compounds according to the invention can be isolated in optically active or racemic forms. Optically active forms can be obtained by separation of racemic forms or by synthesis from optically active starting materials. All methods used to prepare the compounds of this disclosure and the intermediates obtained therefrom are considered part of this disclosure. When enantiomeric or diastereomeric products are obtained, they can be separated by standard methods, such as chromatography or fractional crystallization.

Depending on the conditions of the method, the final products according to this disclosure are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the disclosure. If desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; the salt can be converted into a free compound or another salt; a mixture of isomeric compounds according to this disclosure can be separated into individual isomers.

Pharmaceutically acceptable salts are preferred. However, other salts that may be useful, for example in isolation or purification steps, may be used during the preparation, and thus are contemplated within the scope of the disclosure.

Within the scope of the invention, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound has been modified by forming its salts with an acid or base. For example, pharmaceutically acceptable salts include, but are not limited to, acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate/hydroxymalonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phenylacetate, phosphate/hydrophosphate/dihydrophosphate, polygalacturonate, propionate, salicylates, stearate, succinate, sulfamate, sulfosalicylate, tartrate, tosylate, trifluoroacetate or xinafoate. Because pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, preferably hydrochloric acid. Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be obtained include, for example, ammonium salts and metals from columns I-XII of the periodic table. In some embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be obtained include, for example, primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, cation exchange resins, and the like. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts of the present disclosure can be synthesized from a parent compound containing a basic or acidic group by standard chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of both; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. Lists of suitable salts can be found in AyPep, IM, Ug., ea., Ketipdiop: Tpe bsiepse apa Rgasiise oi Rpagtasu, 22pa Eaiiop, Rpagtaseciisa! Rgezv, I opdop, ShK (2012), the disclosure of which is incorporated herein by reference.

Compounds according to the invention containing groups capable of acting as donors and/or acceptors for hydrogen bonds may be able to form co-crystals with suitable co-crystal formers. These co-crystals can be obtained from compounds according to the given

With the invention according to known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting or contact in a solution of the compounds according to the present invention with a co-crystal former under conditions of crystallization and isolation of co-crystals formed in this way. Suitable co-crystal formers include those described in UMO2004/078163. Therefore, the invention also relates to co-crystals comprising a compound according to the present invention.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures represented by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, UZN, C, 196, 140, 19M, 8B, yar, gr, 855, 360, 125, respectively. The present disclosure includes various isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes such as H, 73C and 120 are present. Such isotopically labeled compounds can be used in metabolic studies (with 17C), kinetic reaction studies (with, e.g., "H or ZH), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tests of drug or substrate distribution in tissue, or in the radiation treatment of patients . In particular, a "ZE" or labeled compound may be particularly desirable for 5REST or RET studies. Isotopically labeled compounds of the present disclosure may conveniently be prepared by following the procedures disclosed in the Schemes or in the Examples and Preparation Examples described below, by replacing the non-isotopically labeled reagent with an easily available isotopically labeled reagent.

Further, substitution with heavier isotopes, especially deuterium (ie, "H or 0) may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life of ip mimo or reduced dosage requirements or improved therapeutic index. It is clear that deuterium in in this context is regarded as a surrogate for a compound according to the present disclosure. The concentration of such a heavier isotope, in particular deuterium, can be determined by an isotopic enrichment factor. The term "isotopic enrichment factor", within the scope of the invention, means the ratio between the isotopic distribution and the natural distribution of the specified isotope. If the substituent in the compound according to the invention is labeled deuterium, such a compound has an isotopic enrichment factor for each determined deuterium atom of at least 3500 (52.5 95 deuterium inclusion on each determined deuterium atom), at least 4000 (60 95th deuterium inclusion), at least 4500 (deuterium inclusion at 67.595), at least 5 000 (75 95th deuterium inclusion), at least 5500 (82.5 90 deuterium inclusion), at least 6000 (90 U5 deuterium inclusion), at least 6333.3 (95 95th deuterium inclusion), at least 6466.7 (97 95 deuterium incorporation), at least 6600 (99 95 deuterium incorporation), or at least 6633.3 (99.5 Ob deuterium incorporation).

Isotopically labeled compounds of the present disclosure may be conveniently prepared by standard methods known to those skilled in the art, or by methods similar to those described herein, using a suitable isotopically labeled reagent instead of the unlabeled reagent used elsewhere. Such compounds have many potential applications, for example, as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to biological targets or receptors, or to visualize the binding of compounds according to this disclosure to biological receptors ip mimo or ip miigo. "Stable compound" and "stable structure" are intended to refer to a compound that is stable enough to survive isolation with a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent. Preferably, the compounds according to this disclosure do not contain groups M-halogen, 5(F)2H or (OH.

The term "solvate" refers to the physical association of a compound of this disclosure with one or more solvent molecules, organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvent molecules in the solvate may be present. in the correct order and/or in the wrong order. The solvate may include a stoichiometric or non-stoichiometric amount of solvent molecules. "Solvate" includes both liquid phase solvates and isolated solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are known in the art.

Within the scope of the invention, "polymorph(s)" refers to a crystalline form(s) having the same

From chemical structure/composition, but different spatial arrangements of molecules and/or ions forming crystals. The compounds of this disclosure may be prepared as amorphous solids or crystalline solids. Lyophilization can be used to obtain compounds of the present disclosure in solid form. "EE" refers to the protein product of the gene for embryonic development of the ectoderm. "RKS2" refers to RoiYusotr repressive complex 2.

The term "RKS2-mediated disease or disorder" refers to any disease or disorder directly or indirectly regulated by RKS2. It includes, but is not limited to, any disease or disorder directly or indirectly regulated by the EEU.

The term "disease or disorder mediated by EEO and/or RAES2" refers to diseases or disorders directly or indirectly regulated by EEO and/or RKS2.

Within the scope of the invention, the term "patient" includes all species of mammals.

Within the scope of the invention, the term "patient" refers to an animal. As a rule, the animal is a mammal. "Patient" also refers to any human or non-human organism that can potentially benefit from treatment with an EEJO inhibitor. Patient also includes, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In some embodiments, the patient is a primate. In other embodiments, the patient is a human. Examples of patients include people of any age with risk factors for cancer.

Within the scope of the invention, a patient is one "in need of treatment" if such patient can benefit biologically, medically, or in terms of quality of life from such treatment (predominantly a human).

Within the scope of the invention, the term "inhibits" or "inhibition" refers to the reduction or inhibition of a given condition, symptom or disorder, or disease, or a significant reduction in the initial activity of a biological activity or process.

Within the scope of the invention, the term "treating" or "treating" any disease/disorder refers to the treatment of a disease/disorder in a mammal, especially a human, and includes: (a) ameliorating the disease/disorder (ie, slowing or stopping or attenuating the development disease/disorder or at least one of its clinical symptoms); (B) treating or correcting the disease/disorder (ie, initiating regression of the disease/disorder, either physically (eg, stabilization of a noticeable symptom), physiological (eg, stabilization of a physical parameter), or both); (c) relief or mitigation of at least one physical parameter, including those that may not be noticeable to the patient; and/or (4) preventing or delaying the onset or development or progression of a disease or disorder in a mammal, particularly when such mammal is predisposed to the disease or disorder but has not yet been diagnosed with it.

Within the scope of the invention, "prevention" or "prophylaxis" covers preventive treatment (ie, prevention and/or risk reduction) of a subclinical disease state in a mammal, in particular, in a human, aimed at reducing the likelihood of occurrence of a clinical disease state.

Patients are selected for prophylactic therapy based on factors known to increase the risk of developing a clinical disease state compared to the general population. Methods of "preventive" therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treating a patient who does not yet exhibit a clinical disease state, while secondary prevention is defined as preventing the recurrence of the same or a similar clinical disease state.

Within the scope of the invention, "reducing the risk" or "reducing the risk" covers methods of treatment that reduce the rate of development of a clinical disease state. Also, methods of primary and secondary prevention are examples of risk reduction. A "therapeutically effective amount" includes an amount of a compound of the present disclosure that elicits a biological or medical response in a patient, such as reduction or inhibition

EEO and/or PKC2, or alleviates symptoms, ameliorates the condition, slows or delays the progression of a disease, or prevents a PKC2-mediated disease or disorder. When it refers to a combination, this term refers to the combined amounts of active ingredients leading to a prophylactic or therapeutic effect, administered in combination, sequentially or simultaneously.

Abbreviations within the scope of the invention are defined as follows: "its" for one-time, "2x" for two-time, "Хx" for three-time, "C" for degrees Celsius, "water." for an aqueous solution, "col." for the column, "eq." for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "l" for liter or liters, "ml" for milliliter or milliliters, "μl" for microliter or microliters, "n." for normal, "M" for molar, "NM" for nanomolar, "mol" for mole, "mmol" for mmol, "min." for a minute or minutes, "hr." for hour or hours, "n" for room temperature, "KT" for holding time, "OM" for overnight period, "atm." for atmosphere, "ri" for pounds per square inch, "conc." for concentrate, "hydr." for an aqueous solution, "saturation." for saturated, "MMU" for molecular weight, "pm/" or "nmame" for microwave, "T.pl." for the melting point, "wt." for mass, "Me" or "Mas. spec." for mass spectrometry, "E5I" for mass spectroscopy with electrospray ionization, "NK" for high resolution, "NKM5" for mass spectrometry with high resolution, "/"СМ5" for liquid chromatography with mass spectrometry, "HPLC" for high-performance liquid chromatography, "CR HPLC" for reversed-phase HPLC, "TI C" or "Ps" for thin-layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "poe" for nuclear Overhauser effect spectroscopy, "IN" for proton , "b" for delta, "c" for singlet, "d" for doublet, "" for triplet, "k" for quartet, "m" for multiplet, "width" for extended, "Hz" for hertz, " en." for "enantiomeric excess," and "a," "B," "B" and EE," and "72" are stereochemical designations known to those skilled in the art.

The following abbreviations used below have their respective meanings:

Вп benzyl v tert-butoxycarbonyl vОосСго di-tert-butyldicarbonate

You are butyl

C8v2bO»z anhydrous cesium carbonate

2,3,4,6,7,8,9,10-octahydropyrimido|1,2-a|)azepine dichloromethane

LOBSTER 4-dimethylaminopyridine

OME dimethylformamide pM5o dimethylsulfoxide

ARRA diphenylphosphorylazide

EA ethyl acetate

KE ethyl

EUN ethanol

EOAc ethyl acetate

NATO 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

NOI hydrochloric acid i-Vi isobutyl i-Ri isopropyl

COAc potassium acetate

SOLDER lithium aluminum hydride

PS lithium chloride yinMO5 lithium bis(trimethylsilyl)amide tSRVA 3-chloroperoxybenzoic acid

Me methyl

Me 1-ViChRIO5 di-tert-butyl(24,6-triisopropyl-3,4,5,6-tetramethyl-|1"1-biphenyl|-2-ilophosphane mesm acetonitrile

MpO" manganese dioxide

Me nitrogen

Mmavna sodium borohydride

Mmansoz sodium bicarbonate

Ma»5O4 sodium sulfate

RP phenyl

RPRiz triphenylphosphine

Pa(arrySi»P,1-bisidiphenylphosphino)ferrocenidichlor palladium (I)

RFI(PP3)4 tetrakis(triphenylphosphine) palladium (0)

RIizR-O triphenylphosphine oxide

And you or you! tert-butyl

TEA triethylamine

TEA trifluoroacetic acid

TNE tetrahydrofuran 7p(SM)" zinc cyanide

IM. SYNTHESIS

Compounds of the present disclosure may be prepared in a number of ways known to those skilled in the art of organic synthesis through the methods, reaction schemes, and examples provided herein. The compounds of this disclosure can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or modifications thereof, understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in a solvent or a mixture of solvents suitable for the reagents and materials used and suitable for the transformations carried out.

A specialist in the field of organic synthesis will understand that the functional groups that are present on the molecule must correspond to the proposed transformations. This will sometimes require changing the order of synthesis steps or choosing one particular process scheme over another to obtain the desired compound according to the present disclosure.

The starting materials are available from commercial sources such as Algiers and Specitas (Milwaukee,

Wisconsin), or can be obtained using methods known to a person skilled in the art (for example, obtained according to the methods generally described in the first review5 R. Riezeg apa Magu Riezeg, Keadepiv og

Ogoapis bupipezviv, u. 1-19, UMieu, New York (1967-1999 ed.), I agosk, V.S., Sotrgepepvime Ogdapis

Tgapviogtaiyop5, 279-ed., UMIeu-MSN Weinheim, Germany (1999), or Weibieip5 Naparisp deg ogdapizspep Spetje, 4, Asia. unit Zrhipdeg-Megiad, Berlin, including supplements (also available through the online database Veii:ieip)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for the synthesis of compounds of the present disclosure as well as key intermediates. For a more detailed description of individual stages of the reaction, see examples section below. It will be apparent to one skilled in the art that other synthetic routes may be used to synthesize the compounds of the invention. Although some starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be used instead to provide a variety of derivatives and/or reaction conditions. In addition, many compounds obtained by the methods described below can be further modified in light of this disclosure using standard chemistry known to those skilled in the art.

In the preparation of compounds according to this disclosure, it may be necessary to protect the removed functional group of the intermediate compounds. The need for such protection varies depending on the nature of the removed functional group and the conditions of the methods of preparation. The need for such protection is easily determined by a specialist. For a general description of protective groups and their use, see

Steepe, T.M. Yei ai., Rgoiesiipd StoyMirz ip Ogdapis Zupipeziv, 4 Eia., Umieu (2007). Protecting groups that are incorporated in the preparation of compounds of the present disclosure, such as a trityl blocking group, may be shown as a single regioisomer, but may also exist as a mixture of regioisomers.

Scheme 1 (below) describes potential routes for the preparation of compounds of the present disclosure

Formulas including compounds (IA). Compounds of Formula (IA) can be made substantially optically pure either by using substantially optically pure starting material or by separation by chromatography, recrystallization, or other separation methods known in the art. For a more detailed description, see examples section below.

Scheme 1 (by tet

To us. Khdith is om. "VMe M. i8Me -M. Metro

Be MNoMNo and SNOME) Yi v

HO ke ho» si MAM» Mm-M 1 2 KI (Jid tO (Tuesday reaction Ka

M chi g GG i conjugation MM sk, ЖИ з

I z set her ve I y - M meE shi I v dya M. x Kor r z 8 y

M-M MAM 4 5

X: Why Mr

According to Scheme 1, 5-chloro- or 5-bromo-substituted 4-chloro-2-(methylthio)pyrimidine 1 was treated with hydrazine to form 5-chloro- or 5-bromo-substituted 4-hydrazinyl-2-(methylthio) pyrimidine 2, which was converted into the cyclized product C after treatment with trimethyl orthoformate or triethoxymethane. C was then treated with a suitable amine to form 4, followed by cross-coupling with a suitable EZ reagent (e.g., a different boronic acid or equivalent with a suitable RZ group) to give product 5.

Also, in some cases, the compounds of the present invention were obtained according to the reaction sequence in Scheme 2. Compound 4 was first protected as 4" and then the combination reaction was carried out with the addition of the KZ group to obtain compound 5'. The final compound 5 was obtained after removing the protecting group of the compound 5'. For a general description of protective groups and their use, see Sgeepe, T.M.

UMiIeu (2007).

Scheme 2 (show Z (clearly r va R te shk protection ! - connection M. M. ut sya AM A i M i i wa ! sany, etc. 00 ---p0 NI nn VNI M;

Mu M Z you "ro M M Ge vt biy M v ya Sho; and vu M M

MM r removal of protection p: zahnena gruna (bu yo

Ba nn GG "M. re M. horror ru their p vu

M-Mm

M in

GENERAL METHODS

The following methods were used in the illustrated Examples, unless otherwise noted.

Purification of intermediate compounds and final products was carried out by either normal or reverse phase chromatography. Normal phase chromatography was performed using pre-filled 5ZiO" cartridges eluting with either hexanes and ethyl acetate or OSM and Meon gradients, unless otherwise noted. For very polar amines, OSM and 1M MNz gradients in Meon were used. Preparative reverse-phase HPLC was performed using C18 columns with UV 214 nm and 254 nm or detection of preparative

IISM5 with elution with gradients of Solvent A (water with 0.195 TEA) and Solvent B (acetonitrile with 0.1 95 TEA) or with gradients of Solvent A (water with 0.05 95 TEA) and Solvent B (acetonitrile with 0.0595 TEA) or with gradients to Solvent A (water with 0.05 95 ammonia) and

Solvent B (acetonitrile with 0.05 95 ammonia).

Methods I C/M5, used in the characterization of examples

Analytical HPLC/M5 with reversed phase was carried out on Adiepi I C1200 systems with Mass spectrometer 6110 (Methods A-O)) or 6120 (Method E and EP) or 6130 (Method c).

Linear gradient from 5 95 to 95 95 V in 1.2 minutes, with 1 minute hold at 95 95 V;

UV visualization at 214 nm and 254 nm

Method A: Column: ZyMipRigeF C18 4.6x50 mm 3.5 μm

Flow rate: 2 ml/min.

Solvent A: trifluoroacetic acid 0.1 95, water 99.9 95

Solvent B: trifluoroacetic acid 0.1 95, acetonitrile 99.9 Or.

Linear gradient from 5 95 to 95 95 V in 1.5 minutes, with 1 minute of maintenance at 95 95 V;

UV visualization at 214 nm and 254 nm

Method B: Column: ХВгидде 8 С18 4.6х50 mm 3.5 μm

Flow rate: 2 ml/min.

Solvent A: water with 10 mM ammonium bicarbonate

Solvent B: acetonitrile.

Linear gradient from 5 95 to 95 95 V in 1.2 minutes, with 1.3 minutes hold at 95 95 V, from 95 95 to 5 905 V in 0.01 minutes;

UV visualization at 214 nm and 254 nm

Method C: Column: ZMPRigeF C18 4.6x50 mm 3.5 μm

Flow rate: 2 ml/min.

Solvent A: trifluoroacetic acid 0.1 95, water 99.9 95

Solvent B: trifluoroacetic acid 0.1 95, acetonitrile 99.9 Or.

Linear gradient from 5 95 to 95 95 V in 1.4 minutes, with 1.6 minutes hold at 95 95 V, from 95 95 to 5 905 V in 0.01 minutes;

UV visualization at 214 nm and 254 nm

Method 0: Column: HVgidde 8 C18 4.6x50 mm 3.5 μm

Flow rate: 1.8 ml/min.

Solvent A: water with 10 mM ammonium bicarbonate

Solvent B: acetonitrile.

Linear gradient from 5 95 to 95 95 V in 1.5 minutes, with 1 minute of maintenance at 95 95 V;

UV visualization at 214 nm and 254 nm

Method E: Column: KhvVgidde 8 C18 4.6x50 mm 3.5 μm

Flow rate: 2 ml/min.

Solvent A: water with 10 mM ammonium bicarbonate

Solvent B: acetonitrile.

Linear gradient from 5 95 to 95 95 V in 1.5 minutes, with 1 minute hold at

Method: 35 V;

I Visualization of UV at 214 nm and 254 nm and 300 nm

Column: ХВгидде Ф С18 4.6х30 mm 2.5 μm

Flow rate: 1.8 ml/min.

Solvent A: water with 0.1 95 ammonia

Solvent B: acetonitrile.

Linear gradient from 10 95 to 95 95 V in 2 minutes, with 1 minute of maintenance at 95 9 V;

UV visualization at 214 nm, 254 nm and 300 nm

Method 0: Column: Zipiige F C18 4.6x30 mm 2.5 μm

Flow rate: 1.8 ml/min.

Solvent A: water

Solvent B: Men with 0.1 95 formic acid

NMR used to characterize Examples

H NMR spectra were obtained with VgyKeg spectrometers with Fourier transformation, operating at frequencies as follows: H NMR: 400 MHz (VgyKeg). "3 NMR: 100 MHz (VgikKeg). Spectral data are in the format: chemical shift (multiplicity, number of hydrogen atoms). Chemical shifts are defined in ppt to the side of the weak field of the internal standard tetramethylsilane (b units, tetramethylsilane-:0 parts per million) and /or with an indication of the peaks of the solvents, which in the spectra of "H

NMRs appear at 2.49 parts per million for CO2NOOSOYU, 3.30 parts per million for

CO2hNOI, 1.94 for COzZSM and 7.24 parts per million for COSiz, and which appear in the C NMR spectra at 39.7 parts per million for COz5OSO", 49.0 parts per million for COzOO and 77.0 parts per million for SOSIz. All "3 NMR spectra were with an unbound proton.

M. EXAMPLES

The following Examples were obtained, isolated and characterized using the methods disclosed herein. The following examples illustrate the partial scope of the disclosure and are not intended to limit the scope of the disclosure.

Unless otherwise noted, source materials are available from non-exclusive commercial sources such as TSI Ripe Spetis!5 (Japan), Zpapopai Spetnpege So., Tsa. (Shanghai, China), Ayigoga Ripe

Spetisa!5 GIS (San Diego, California), ESN Sgoimr (Ukraine), Ayagispy Spetisa!5 So. (Milwaukee,

Wisconsin), I apsazieg Zupipeviv, Ips. (Windham, MN), Asgo5 Ogdapis5 (Fairlawn, NJ),

Maubgidde Spetis!I Sotrapu, tsa. (Cornwall, England), Tudeg zsiepiys (Princeton, New Jersey)

Aviga/epesa RIiaptasetsshiisa!5 (London, England), Spetbgidde Sogrogayop (USA), Maighih Zsiepiyis (USA), Sopieg Spet 8 Rpagt So., Tsya (China), Epatipe CI (Ukraine), Sotri-Viosk»5, Ips. (Dignity-

Diego, USA), OaKooai Rgodisiv, Ips. (USA), Aroio 5siepiyis (Y. (Great Britain), AiPispet | I. S. (USA) and OKgogdzupie?7 tsa (Latvia). RpappavViosk KUO So. a (Nanjing, China), Asseia SpetVio

Co. Tsa (Shanghai, China), AIrshop Ips. (Shanghai, China), UC zsiepiyis | and. (Beijing, China).

INTERMEDIATE COMPOUNDS

Intermediate compound 3: 8-bromo-5-(methylthio)-P1,2,4A|triazolo|4,3-s|Ipyrimidine pr tok pe» more VG i» ve 2

NM. MA

SI MN M

1 2 KI 5-Bromo-4-hydrazinyl-2-(methylthio)pyrimidine (2): To a solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (1, 49.0 g, 0.205 mol) in ethanol (1000 ml) was added hydrazine (21.5 g, 0.430 mol). The reaction mixture was stirred at room temperature for 4 h. The obtained suspension was filtered, washed with hexane and dried in a vacuum to obtain the target compound (44.1 g, 92 95) in the form of a white solid, "H-NMR (400 MHz, OM50O-av) mp 2.42 (s, ZN), 8.08 (s, 1H). I! SM: (M-A-NI-234.9; 236.9.

Intermediate 3: 5-bromo-4-hydrazinyl-2-(methylthio)pyrimidine (2) (40.0 g, 0.17 mol) was dissolved in 200 mL of triethoxymethane. The mixture was heated under reflux and stirred for 3 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by flash chromatography (EA: РЕ-1:15-41:1) to obtain the target compound (38.3 g, 92 95) in the form of a white solid. "H-NMR (400 MHz, methanol-aa) b ppt 2.82 (s, 3H), 8.03 (s, 1H), 8.87 (s, 1H). I SM: (M-ANI-245 ,0; 247,0.

Intermediate compound A1: 8-bromo-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine

Ve

Ve Vg Vg E. r

E. And even more T in: Zv I -- p Me U zm ! 4 |ts and it is food and -y -yah on - o G and eco) ipltu

Alya dida digh

NM. basic cm whale, RE. гг эр ден It's fashionable with anoy

A15 Az ATZ 2-Bromo-4-(2,2-diethoxyethoxy)-1-fluorobenzene (A1.1): To a solution of 3-bromo-4-fluorophenol (500 g, 2.62 mol) and 2-bromo-1 ,1-diethoxyethane (670 g, 3.4 mol) in 2.0 L of OME was added CoCO3 (1085 g, 7.86 mol) in one portion. The suspension was heated at 110 C and stirred overnight in an M2 atmosphere. After cooling to room temperature, the reaction mixture was diluted to 10.0 l

NgO and extracted with EIUAs (2.0 L x 3). The combined organic phase was washed with brine twice, dried over anhydrous Ma»5O», filtered and concentrated under reduced pressure.

The residue was purified on silica gel (EuAc/hexane-0:100-5:100) to obtain the target compound (810 g, 80 95) in the form of a yellow oil. "H-NMR (400 MHz, methanol-az) b ppt 1.27 (t, 6 H), 3.65 (Kk, 2 H), 3.78 (k, 2 H), 3.97 (d, 2 H), 4.82 (t, 1 H), 3.97 (d, 2 H), 6.84 (dd, 1 H), 7.04 (dd, 1 H), 7.13 (d, 1 H). 4-Bromo-5-fluorobenzofuran (A1.2a together with regioisomer A1.25): To a solution of PPA (1324 g, 3.93 mol) in toluene (2.0 L) was added A1.1 (810 g , 2.62 mol) in 30 minutes at 95 26. The reaction mixture was stirred at 95 "C for 2 hours. After cooling to room temperature, 4.0 L of ice water was slowly added. The mixture was extracted with PE (2.0 L x 2), the combined organic phase was washed with brine (2.0 L x 2), dried over anhydrous NaCl, filtered and concentrated under reduced pressure. The residue was purified on silica gel (EuAcC/PE-0:100-5:100) to obtain a mixture of A1.2a and A1.2p6 (A1-ha: A1-26-1:0.7, 310 g, 55 95th yield ) in the form of yellow oil.

B-Fluorobenzofuran-4-carbonitrile (A1.4): To a mixture of A1.2a and A1.25 (310 g, 1.44 mol) and 7p(SM)" (253 g, 2.16 mol) in 1.0 l OME was added Pa(RRIII)4" (162 g, 0.14 mol) under an atmosphere of Me".

The reaction mixture was heated at 100 °C and stirred for 18 hours. After cooling to room temperature, the mixture was diluted with 5.0 L of water and extracted with EIOAc (1.0 L x 2). The combined organic phase was washed with saline solution (1 L), dried over Ma»5O4 (anhydrous), filtered and concentrated under reduced pressure. The residue was purified on a column for flash chromatography (mobile phase: EtOAc/PE-1:70 for 30 minutes, retention time - 11 minutes, flow rate: 120 ml/min) to obtain the target compound (92 g, 40 95) in in the form of a white solid. "H-NMR (400 MHz, methanol-da) b ppt 7.07 (d, 1H), 7.40 (dd, 1H), 7.89 (dd, 1H), 8.10 (dd, 1H). tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)ucarbamate (A1.4): To a solution of A1.4 (44.5 g, 276.4 mmol) and VosgO (90.0 g, 414.6 mmol) in 1.0 L of MeonH was added Ra/s (5 g, 10 wt. 90). The reaction mixture was degassed with He and stirred under an atmosphere of H2 overnight. The mixture was filtered through celite, washed with MeonH (300 mL x 2), the filtrate was concentrated under reduced pressure. The residue was recrystallized from PE to give the target compound (61.0 g, 93 95) in the form of a white solid. "H-NMR (400 MHz, OM50-av) b mp 1.48 (c, 9H), 3.21 (t, 2H), 4.12 (d, 2H), 4.53 (t, 2H), 6.63 (dd, 1H), 6.86 (dd, 1H) , 7.25 (with width, 1H). HOM: |M- "VINI -212.1. (5-Fluoro-2,3-dihydrobenzofuran-4-yl)uhexamethylenetetramine (A1.5): solution of A1.4 (18.3 g, 68.5 mmol) in 50 ml of NeSi/dioxane (4 mol/l) was stirred at room temperature for 4 h.

The mixture was concentrated under reduced pressure. The residue was diluted with a mixture of solvents (MeOon:Mesm-1:10, 500 ml), then KCO3 (18.0 g, 342.5 mmol) was added. The mixture was heated at 60 °C and stirred for 3 h, cooled to room temperature, filtered and concentrated under reduced pressure. The crude product was purified on silica gel (Meon:

EtOAc-0:100-1:4) to obtain the target compound (9.2 g, 80 95) in the form of a yellow oil. "H-NMR (400 MHz, methanol-adya) b ppt 3.27 (t, 2H), 3.77 (s, 2H), 4.56 (t, 2H), 6.59 (dd, 1H), 6.81 (dd, 1H).

SM: (MANI -168.1.

E Z

My 00 М M ХА t y - MN... p

Shk E and b Se

Вб у; Kn | She r Z r W Kk -

M-M what MAM with di. yes

Intermediate A: A mixture of A1 and 1.5 (1.1 g, 8.2 mmol) and 8-bromo-5-(methylthio)-

P1,2,4Hygriazolo|4,3-s|Ipyrimidine (3) (1.0 g, 4.1 mmol) was heated at 40 "С and stirred for 16 h. After cooling to room temperature, the mixture was diluted with E(AcС (35 ml).

The precipitate was filtered and washed with E(OAc (3 ml x 3), dried in vacuo to give the target compound (1.0 g, 67 90) as a white solid. "H NMR (500 MHz,

OM59) b ppt 3.27 (t, 2H), 4.53 (t, 2H), 4.66 (d, 2H), 6.71 (dd, 1H), 6.95 (t, 1H), 7 .85 (s, 1H), 8.75 (t, 1H), 9.48 (s, 1). CM: MANI -363, 7; 365.7.

Intermediate compound A2: 8-bromo-M-(2,3-dihydrobenzofuran-4-yl)umethyl)-(1,2,4)griazolo|4,3- cIpyrimidin-5-amine (2,3-dihydrobenzofuran-4 -yl)methanamine A2.4: he i nm chn i Ж se Fo xx dt

Se - SO - 03 - so ns veka: oh oh

Ag Ag2.2 Ag (E)-Benzofuran-4-carbaldehyde oxime (A2,1): a mixture of benzofuran-4-carbaldehyde (5 g, 34.2 mmol), MH2OH.HCl (4.72 g, 68.4 mmol ) and Mahon (5.47 g, 136.8 mmol) in NaCl (75 ml) and water (75 ml) were heated to 25 °C and stirred for 3 h. The mixture was concentrated, the residue was diluted with EA (150 ml), the organic layer washed successively with other NSI (100 ml x 2), sat.

Manso:z (100 mL x 2) and brine (100 mL), dried over Mg 5 O, filtered and concentrated to give the title compound (5 g, 9095) as a white solid. HOM: (MANI -162.0.

Benzofuran-4-ylmethanamine (A2.2): A mixture of A2.1 (5 g, 31 mmol), MNa.OH (43 mL), and Raney's Me (2.66 g, 31 mmol) in CH3ZOH (585 mL) was stirred at 20 "C for 16 hours in an atmosphere of No".

The mixture was filtered and the filtrate was concentrated to give the target compound (4.2 g, 92 95) as an oil. I SM: (MANI -148.1. (2,3-dihydrobenzofuran-4-yl)ugexamethylenetetramine (A2.4): a mixture of A2.2 (2.2 g, 15 mmol), Ra/C (2 g, mass . 95:10 95) and SNHZON (40 ml) were heated to 48 "C and stirred for 16 h under an atmosphere of Ma". The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the target compound (2 g, 90 95) . "H NMR (400 MHz, SOSIz") b ppt 3.20 (t, 2H), 3.84 (s, 2H), 4.60 (t, 2H), 6.72 (d, 1H), 6 .85 (d, 1H), 7.13 (t, 1H).

VG i Y | I am in UM

Ms. Mrs. WE; and at MM 3 d23 to

Intermediate Ag: The target compound was obtained by a method similar to that used

Zo for obtaining AT, by replacing (5-fluoro-2,3-dihydrobenzofuran-4-yl-hexamethylenetetramine (A1.5) with A2.4. "H NMR (400 MHz, OM5O) 5 ppt 3.19 (t, 2H) , 4.50 (t, 2H), 4.64 (s, 2H), 6.68 (d, 1H), 6.84 (d, 1H), 7.05 (t, 1H), 7.81 ( s, 1H), 9.48 (s, 1H). EM: (MANI -346.0.

Intermediate compound AZ: 8-Bromo-M-(2-methyl-2,3-dihydrobenzofuran-4-ylylmethyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine

Oho. oh, put on nya Kon Ah u ono, Zh v 0-2 - 0-0.

Az Az t ry r M ro ch siv, ol o i dz Az AZA

Methyl 2-(prop-2-yn-1-yloxy)benzoate (AZ.1): To a solution of methyl 2-hydroxybenzoate (3.0 g, 19.72 mmol) in OME (20 ml) was added 3-bromoprop -1-yne (6 ml, 19.72 mmol) and K»CO3 (8.18 g, 59.2 mmol). The mixture was stirred at 20 "C overnight, diluted with TMF and washed with water (80 ml x 3). The organic layer was dried over Mag25O04 and concentrated. The residue was purified by flash chromatography, triturated with a mixture of EA/hexane -10 95 to give the target compound (3, 0 g, 90 Fe). "H NMR (400 MHz, SOS") b ppt 2.53 (s, 1H), 3.90 (s, ЗН), 4.10 (s, 2H), 7.06 ( t, 1H), 7.15 (d, 1H), 7.48 (t, 1H), 7.82 (d, 1H). HOM: MANI -190.9.

Methyl 2-methylbenzofuran-7-carboxylate (AZ.2): A mixture of AZ.1 (1.0 g, 5.26 mmol) and cesium fluoride (1.038 g, 6.84 mmol) in M,M-diethylaniline (5 ml, 5.26 mmol) was irradiated in a microwave reactor at 2002C for 30 minutes. After dilution with ether, insoluble materials were removed by decantation. The crude products were separated by column chromatography using a mixed solvent of hexane and ethyl acetate (10:1, v/v) to give the target compound (500 mg, 50 95). "H NMR (400 MHz, SOSIizv) b ppt 2.55 (s, ЗН), 4.01 (s, ЗН), 6.44 (s, 1Н), 7.22-7.27 (t, 1Н) , 7.66 (d, 1H), 7.86 (d, 1H). And C-mM5: (M-A-NI -191.0. (2-Methylbenzofuran-7-yl)umethanol (AZ.4) : To a solution of AZ.2 (1.0 g, 5.26 mmol) in TNE (3 mL) was added HyAlIINa (10.52 mL, 10.52 mmol). The mixture was stirred for 1 h at 02С and warmed to room temperature for 2 hours, quenched with a 1M solution of HCl and filtered, concentrated to obtain the target compound in the form of a crude product, which was used in the next stage without additional purification. 4--(Azidomethyl)-2-methylbenzofuran (AZ.4): To the stirred to a solution of AZ.4 (350 mg, 2.158 mmol) in toluene (10 mL) was added ORPA (683 mg, 2.482 mmol). The reaction mixture was cooled to 0 "С, and OVI (0.390 mL, 2.59 mmol) was added dropwise. Reaction the mixture was allowed to warm to room temperature and stirred under an M2 atmosphere overnight. The mixture was acidified to rneB5-6 In. NS, then extracted with EAs. The aqueous phase was neutralized with sat. therefore, EUAs were extracted. The combined organic phase was washed successively with NaHCO3 and saline solution, dried and concentrated, the residue was purified by column chromatography (5 Fo

ECOAcC in hexane as eluent) to give the target compound (200 mg, 50 95) as a colorless liquid. "H NMR (400 MHz, SOSI") b ppt 2.49 (s, ЗН), 4.64 (s, 2Н), 7.15-7.17 (t, 2Н), 7.45-7.48 (t,

Co., Ltd.) 1H). (2-methylbenzofuran-4-yl)ugexamethylenetetramine (AZ.5): To a solution of AZ.4 (50 mg, 0.267 mmol) in TNE (5 ml) and water (0.2 ml) was added PP" (140 mg, 0.534 mmol). The mixture was stirred at 25 °C for 2 h, concentrated under reduced pressure, the residue was purified by flash chromatography to obtain the target compound (30 mg, 70 90) in the form of a colorless oil. /EA, and the amine was released in 20 u5-th OSM/MeOHn.) and CM5:

IMANG-162.1. (2-Methyl-2,3-dihydrobenzofuran-4-yl)ugexamethylenetetramine (AZ.6): To a solution of AZ.5 (100 mg, 0.372 mmol) in methanol (10 ml) was added hydrochloric acid (0.1 ml, 3 .29 mmol) and Pa/cС (10 95) (39.6 mg). The reaction mixture was stirred at 509C for 12 hours. in a hydrogen atmosphere, filtered and concentrated. The residue was purified by flash chromatography (OSM:MeOH-10:1) to give the target compound (60 mg, 50 95). "H NMR (400 MHz, Meob) b ppt 1.41-1.47 (t, 3H), 2.76-2.91 (t, 1H), 4.05 (s, 2H), 4.93- 5.00 (t, 2H), 6.74-6.79 (t, 1H), 6.88 (d, 2H), 7.16-7.18 (t, 1H).

SM: (MANI -164.1.

in br» sh Mer s a, om : shk SCHO 0 -- o, x

M-M ke M-ki 3 AZb Az

Intermediate AZ: The target compound was prepared by a method similar to that used to prepare Intermediate Ai7. by replacing (5-fluoro-2,3-dihydrobenzofuran-4-yl-hexamethylenetetramine (A1.5) with AZ.6. "H NMR (methanol-a") 6: 1.40-1.47 (t, ЗН), 2.75-2.90 (t, 1H), 3.45-3.44 (t, 1H), 4.71 (d, 2H), 4.93-4.98 (t, 1H), 6, 63-6.79 (t, 1H), 6.87-6.90 (t, 1H), 7.04-7.16 (t, 1H), 7.86 (d, 1H), 9.40 ( d, 1H). I EM: (MANI -359.7.

Intermediate compound B (boronic acid or ester that is not commercially available for the synthesis of compounds in Table 2). 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (B1)

A AT 1 "y - - 3 NM I -f I --7 the same; Me "the same field as LANGUAGES You 2 I M ЗзЩy. al vi4 vi vi vi vi vi vi 5-Bromo-2,6-dimethylpyrimidine-4 -ol (B1,1): Bromine (153.4 g, 0.96 mol, 1.2 equiv.) was added dropwise to a solution of 2,6-dimethylpyrimidin-4-ol (100 g, 0.8 mol, 1, 0 equiv.) in 1.0 l of chloroform.

The mixture was then stirred at 50°C overnight. After cooling to room temperature, the excess solvent was evaporated and 500 mL of ethyl acetate was added, which was removed again under reduced pressure. This process was repeated three times. The yellow solid was stirred in 100 mL of ethyl acetate for 30 minutes at room temperature. After filtration, the residue was washed with ethyl acetate (100 mL x 2) to give the target compound (135 g, 82 95) as a white solid. I EM: (MANI -205.2. 5B-Bromo-4-chloro- 2,6-dimethylpyrimidine (81.2): a mixture of B1.1 (134 g, 0.66 mol) in 500 ml of ROS" was stirred at 110 "C for 18 h. The excess of ROS was removed under vacuum, the residue was poured into 1000 g of crushed of ice. Then solid ManHCO3 was added carefully to bring the pH to 8-9. The aqueous layer was extracted with ethyl acetate (1.5 L x 3), and the combined organic layers were washed with brine (1.0 L x 2), dried over Mg5O" 54, concentrated to obtain the target compound (71 g, 48 95) in the form of a solid milky substances of white color. SM:

IMANI-223.0. 5B-Bromo-4-hydrazinyl-2,6-dimethylpyrimidine (81.4): A solution of B1.2 (70 g , 0.32 mol) in 350 ml of methanol dropwise at 0 C. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, the residue was diluted with 500 ml of water,

Z was extracted with SNCl (500 ml x 3). The combined organic layers were washed with brine (500 mL), dried over Mag25O5 and concentrated to give the target compound (63 g, 91 95) as a yellow solid. I SM: (M--NI-219.0. 5-Bromo-2,4-dimethylpyrimidine (81.4): A solution of B1.4 was added to a suspension of MpO" (96 g, 1.1 mol) in 1.0 l of CHS (47 g, 0.22 mol) in 1.0 L of CH3S dropwise at 0 "C. The mixture was stirred for 2 h at room temperature. After filtration and concentration, the residue was purified on a 100-200 mesh silica gel column (PE-' EA-100:0-50:50) to obtain the target compound (30 g, 73 90) in the form of a yellow solid substance. SM: (MANI -189.1.

Intermediate B1: a mixture of B1.4 (12 g, 64 mmol), bis(pinacolato)diboron (22.8 g, 89.6 mmol, 1.4 equiv), COAc (18.8 g, 192 mmol, 3 .0 equiv.) and RasarrosSi" (2.34 g, 3.2 mmol) in 200 ml of anhydrous dioxane were heated at 90 "C and stirred for 4 h in a Me atmosphere.

The solvent was removed under reduced pressure, the residue was diluted with 300 ml of mixed solvent (REEA-4:1), filtered and concentrated. The crude product was purified by flash chromatography (REEA: 2:1 to 1:1) to give the target compound (10 g, 66,906) as a yellow oil.

SM: MANI -235.1.

Intermediate B2: (1-Isopropyl-3-methyl-1H-pyrazol-4-yl)boronic acid

Vg z x, V x t | B

Zh -A- M. i --x y Z i / M M. n ra Shcher re v e2 4-Bromo-1-isopropyl-3-methyl-1H-pyrazole (82.1): a mixture of 4-bromo-3 -methyl-1H-pyrazole (2 g, 12.5 mmol), 2-iodopropane (6.37 g, 37.5 mmol), С52СО3 (6.25 g, 50 mmol) and acetonitrile (30 ml) were stirred at 902С within 12 hours The reaction mixture was filtered with Meon (15 mL) and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (UF214,

RE:OMS-from 100:1 to 50:50) to give the target compound (700 mg, 56 95) in the form of a clear oil. And SM: (M.--NI-203,1.

Intermediate compound B2: To a solution of 82.1 (202 mg, 1.0 mmol) in TNE (5 ml) was added n-VIII and (0.5 ml, 1.2 mmol, 2.4 M in TNE) in an M2 atmosphere at - 782S. The reaction mixture was stirred at -78 2

C for 30 minutes, and then triisopropyl borate (564 mg, 3.0 mmol) in TNE (2 mL) was added dropwise with stirring at -787 C. The mixture was stirred at -78? C for 2 hours. The mixture was quenched with water (3 ml), the aqueous layer was purified by flash chromatography (silica gel, UF214,

МНаАНСОзиводавзмМмеонН-0.5М100М1) to obtain the target compound (100 mg, 60 95) in the form of a white solid. And SM: (Man -169.1.

Intermediate compound B3: 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)upyridin

M roya

5-Bromo-2-methoxy-4-methylpyridine (83.1): Sodium (4.8 g, 0.2 mol) was added in portions to 80 ml of a stirred CH2OH solution . After addition, pure 5-bromo-2-fluoro-4-methylpyridine (7.6 g, 40 mmol) was added. The clear solution was then stirred at room temperature overnight. The reaction mixture was quenched with water (400 ml), extracted with dichloromethane (300 ml x 3). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the target compound (6.95 g, 86 95) as a pale yellow solid. "H NMR (500 MHz, SOSI") b 2.41 (s, ЗН), 3.87 (s, ЗН), 6.61 (s, 1Н), 8.15 (s, 1Н).

Intermediate BZ: The target compound was obtained by a method similar to that used for the preparation of Intermediate B1, by replacing B1.4 with B3.1. GSM5: MANI -250.1.

Intermediate compound B4: b-cyclopropyl-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)upyridin u r z o VE o Ve She V. ch F pro i vn i av chiv ON dnu i ekh pn St

Bg M My Ku; M from BI. in 3-Bromo-6-cyclopropyl-2-methylpyridine (84.1): a mixture of 3,b-dibromo-2-methylpyridine (250 mg, 1 mmol), cyclopropylboronic acid (86 mg, 1 mmol), C52CO3 (975 mg, C mmol), RA(PP3)4 (160 mg, 0.2 mmol) and dioxane (5 mL) were stirred at 1202 under M" under microwave heating for 30 minutes. The mixture was filtered with Meon (15 ml), the filtrate was purified by preparative TIS (silica gel, UF254, PE) to give the target compound (100 mg, 47 95) in the form of a clear oil. "H NMR (400 MHz, SOSI»z) b ppt 0.95-0.98 (t, 4H), 1.46-1.99 (t, 1H), 2.56 (s, ЗН), 6, 76 (d, 1H), 7.59 (d, 1H).

Intermediate BA: The target compound was prepared by a method similar to that used to prepare Intermediate B1 by substituting B1.4 for B4.1. And EM: (MANI -260.4.

Intermediate compound B5: 2-((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)pyridine: o sl z В r: ra u С С ше g | and r: I

Zm She «dnei m-n ZM - TV MD - TV university university in B

3-Bromopicolinaldehyde (85.1): A mixture of 3-bromo-2-methylpyridine (5 g, 29 mmol), ZeOg (17.5 mg, 116 mmol) in dioxane (70 mL) was heated to 1202C and stirred for 18 h. The mixture was concentrated and purified by silica gel (PE:EA:-4:1) to give the target compound (3 g, 55 g) as a white solid. I SM: (MANI: -188.1. (3-Bromopyridin-2-yl)methanol (85.2): To a mixture of B5.1 (1 g, 5.4 mmol) in MeOH (20 mL) and TNE (10 mL ) was cooled to 0 C, MaVNaea (0.82 g, 21.6 mmol) was added in portions. The mixture was stirred for 4 h at room temperature. The mixture was concentrated, diluted with water (40 mL), extracted with OSM (40 mL x 3), the organic layer was washed with saline, dried over Mag5O", filtered and concentrated to obtain the target compound (1 g, 99 95) in the form of a white solid. SM: (MANI -190.0.

3-Bromo-2-((tert-butyldimethylsilyl)oxy)methyl)pyridine (85.4): mixture B5.2 (1 g, 5.4 mmol),

LOBSTER (0.33 g, 1.08 mmol), TVZSI (0.97 g, 6.48 mmol) and imidazole (0.48 g, 7 mmol) in OSM (30 mL) were stirred for 18 h. at room temperature. The mixture was diluted with OSM (50 ml), washed with water (30 ml) and saline solution (30 ml), dried over Mag5O»4, filtered and concentrated, the residue was purified on silica gel (RESEA-100:0-50:50) to obtain the target compound (1.1 g, 68 95) in the form of a colorless oil. And SM: (MANI -304.0.

Intermediate B5: The target compound was prepared by a method similar to that used to prepare Intermediate B1 by substituting B1.4 for B5.4. AND! CEM5: MANI -350.1.

Intermediate compound Bb: 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole y x washed y

M

Nn

Vb

A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 45 mmol), iodomethane (9.6 g , 67.5 mmol), K»CO3 (15.5 g, 112.5 mmol) in acetone (50 ml) was stirred at 602С for 12 h. The reaction mixture was filtered, washed with mMeonN (35 ml), the filtrate was concentrated to give the target compound (8 g, 75905) as a white solid. And SM: |(MaANI -237.2.

Intermediate compound B7: 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

From yl)pyridine

Her - o sti VI She Vg po V eh 1 HM I sho Ts AK «E

E E

5 87 in? 3-Bromo-2-(difluoromethyl)pyridine (87.1): To a solution of 33-bromopicolinaldehyde (85.1) (3.0 g, 16.1 mmol) in SOCM (20 mL) was added SUABT (5.2 g, 32.2 mmol) at 02С. The reaction mixture was stirred at 02C for 2 hours. in an atmosphere of M", then a solution of NaHSO: was added in an ice bath. The mixture was extracted with SOHC (60 mL), the organic layer was dried and concentrated.

The residue was purified by flash chromatography to give the target compound (2.5 g, 75 90) as a gray solid, which was used in the next step without further purification.

Intermediate B7: The target compound was obtained by a method similar to that used for the preparation of Intermediate B1, by replacing B1.4 with B7.1. The crude product was used in the next step without additional purification.

Intermediate compound B8: 2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)upyrimidine

N I a: 7

NM. MN. I have you you and you A na D--- Ah know what A He - ra dec NA o dk ud (y su MOSS tm vv wa vi. s. she sht : re re kh niv we

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2-cyclopropyl-b6-methylpyrimidin-4-ol (88.1): a mixture of cyclopropane-carboximidamide hydrochloride (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16 .7 mmol) and CH2OMa (1.8 g, 33.4 mmol) in Men (200 mL) were stirred at room temperature for 18 h. Then the mixture was diluted to saturation. Mag5Oz (50 ml), then concentrated under reduced pressure. The residue was dissolved in 50 ml of water, acidified to pH 4. After cooling to 52C, the solid was collected and dried in vacuo to give the target compound (2.0 g, 98 90) as a yellow solid. The crude product was used in the next stage without further purification. CM: MANI -151.2. 5-Bromo-2-cyclopropyl-6-methylpyrimidin-4-ol (88.2): to a mixture of B8.1 (2.0 g, 13.3 mmol) and

KOH (744 mg, 13.3 mmol) in HgO (15 mL) was added Vig (0.7 mL) at 0 C. The reaction mixture was stirred at room temperature for 2 h. The solid was filtered to give the target compound (1.5 g, 57 90) as a white solid. The crude product was used in the next step without additional purification. I SM: (MANI -231.0. 5-Bromo-4-chloro-2-cyclopropyl-b-methylpyrimidine (88.4): to a mixture of B8.2 (1.5 g, 6.55 mmol) and

OME (1.26 ml, 16.38 mmol) in toluene (20 ml) was added dropwise to a solution of ROSi3 (0.72 ml) in toluene (5 ml) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. then poured in MgCO3 (1M, 30 mL), extracted with EA (20 mL x 3). The combined organic phase was concentrated to give the target compound (1.0 g, 62 95) as a yellow oil. The crude product was used in the next step without additional cleaning. And CM: (MANI: -248.9.

M'-(5-Bromo-2-cyclopropyl-b-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide (88.4): a mixture of B8.4 (1.0 g, 4.06 mmol), 4-methylbenzenesulfonohydrazide (2 .6 g, 13.8 mmol) in CHCl3 (50 ml) was stirred at 902C for 16 h. The solid was filtered off and washed

OSM (5 mL) to give the target compound (0.60 g, 37.5 95) as a white solid

From the color The crude product was used in the next stage without further purification. And SM:

IMANI-397.0. 5-Bromo-2-cyclopropyl-4-methylpyrimidine (88.5): A mixture of B8.4 (600 mg, 1.51 mmol) in MgSO 3 (8 mL, 4.53 mmol) was stirred at 902C for 1 h. The mixture was diluted with EA (20 ml).

The organic phase was separated and concentrated to give the target compound (200 mg, 62 95) as a brown oil. The crude product was used in the next step without additional purification. And SM: NAMES -213.0.

Intermediate B8: The target compound was prepared by a method similar to that used to prepare Intermediate B1 by substituting B1.4 for B8.5. The crude product was used in the next step without additional purification. And SM: (MANI -261.2.

Intermediate compound BO: (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)/boronic acid o E E HO

SV vv y / uh i

Y M SHLE I and M

M -0--k r

M We M! times ve 4-Bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (89.1): the target compound was obtained by a method similar to that used for the preparation of B7.1, by replacing 3-bromopicolinaldehyde (85.1) with 4-bromo -1-methyl-1H-pyrazole-3-carbaldehyde. "H NMR (400 MHz, COSiz) b ppt 3.91 (s,

ZN), 6.66 (t, 1H), 7.43 (c, 13). SM: (MANI -213.1.

Intermediate B0: The target compound was obtained by a method similar to that used for the preparation of Intermediate B2, by replacing 4-bromo-1-isopropyl-3-methyl-1H-pyrazole (82.1) with B9.1. And EM: (MANI -177.2.

Intermediate compound B10: 2-isopropoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine g

5-Bromo-2-isopropoxy-4-methylpyrimidine (810.1): To a solution of 5-bromo-2-chloro-4-methylpyrimidine (3 .0 g, 14.5 mmol) in TNE (30 mL) was added Mann (1.74 g, 44 mmol), the mixture was stirred at room temperature for 0.5 h. Then propan-2-ol (2.6 g , 44 mmol), the mixture was stirred at room temperature for 3 h. The mixture was concentrated, the residue was diluted with water (20 ml), extracted with EA (20x3 ml). The organic layer was dried and concentrated, the crude product was purified by flash chromatography (silica gel;

EA:PE-1:4) to obtain the target compound (2.8 g, 83 95)) in the form of a gray solid. And SM: (MANI -231.0; 232.9.

Intermediate B10: The target compound was prepared by a method similar to that used for the preparation of Intermediate VI by replacing B1.4 with B10.1. ! CM5:

IMANI-279 4.

Intermediate compound B11: 2-(Difluoromethoxy)-4-methyl-5-(4,4,5,5-tetramethyl-1,9,2-dioxaborolan-2-yl)pyridine and g | 5B-Bromo-2-(difluoromethoxy)-4-methylpyridine (811.1): To a solution of 5-bromo-4-methylpyridine -2-ol (8 g, 42.55 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (9.1 g, 51.06 mmol) in 40 ml of SNISM was added Mag»5Ox (606 mg, 4.255 mmol) in one part. The suspension was stirred at room temperature overnight, then concentrated under vacuum, and the residue was purified

Zo on silica gel (PE/EUAs-0-9 95) to obtain the target compound (500 mg, 37 95) in the form of a yellow oil. "H NMR (500 MHz, OM5O-dv) b 2.49 (s, ЗН), 7.19 (s, 1Н), 7.51-7.80 (t, 1Н), 8.49 (s, 1Н ).

SM: IM-ANI -239.9.

Intermediate B11: The target compound was obtained by a method similar to that used for the preparation of Intermediate VI by replacing B1.4 with B11.1. CM5:

IMANI-286.2.

Intermediate compound B12: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)upyrrolidin-2-one o o i. o VG se VES S Si o t zrme an M sty V-o v

YN Yu about Her I also MMI

B121 12 1-(5-Bromopyridin-3-yl)pyrrolidin-2-one (812.1): a mixture of 3,5-dibromopyridine (500 mg, 2.1 mmol), pyrrolidin-2-one (170 mg, 2.0 mmol), CaCO3 (1.04 g, 7.56 mmol), Si! (4 mg, 0.021 mmol),

M1,M1,M2,M2-tetramethylethane-1,2-diamine (3 mg, 0.021 mmol) and dioxane (10 ml) were stirred at 1102C for 12 h. 30 ml of H2O was added to the mixture and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with water (25 mL x 3) and brine (20 mL x 3), dried over Mag25054, concentrated and purified by flash chromatography (silica gel, 40 g,

UV254, PE/EA: 100/1 to 2/1) to give the target compound (240 mg, 47 95) as a gray solid. GSM5: |(MaNI-243.1.

Intermediate B12: The target compound was prepared by a method similar to that used to prepare Intermediate VI by replacing B1.4 with B12.1. ! CM5:

IMANI-206.2.

Intermediate compound B13: 3-(3-(methylsulfonyl)/propoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

NOM j i VE You are the child of the day V oi eoohOVe o By - ot

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M M Bai zm vti visa visa

3-Bromo-5-(3-bromopropoxy)pyridine (813.1): a mixture of 5-bromopyridin-3-ol (500 mg, 2.87 mmol), 1,33-dibromopropane (870 mg, 4.31 mmol), Mann (230 mg, 5.74 mmol) and OME (10 ml) were stirred at 02С for 12 h. Water (10 ml) was added to the mixture, EA was extracted (10 ml x 3), the extracts were washed with water (25 ml x 3) and saline (20 ml x 3), dried over Mag5O0", concentrated and purified by flash chromatography (silica gel , 40 g, PE/EA: from 100/1 to 2/1) to obtain the target compound (300 mg, 36 90) in the form of a gray solid. HOM: (MANI -296.0.

3-Bromo-5-(3-(methylsulfonyl)propoxy)pyridine (813.2): mixture B13.1 (300 mg, 1.02 mmol),

MaozosnH: (156 mg, 1.53 mmol) and OM 5 O (2 mL) were stirred at room temperature overnight. 10 ml of water was added to the mixture, extracted with ethyl acetate (10 ml x 3), the organic layers were washed with water (25 ml x 3) and saline (20 ml x 3), dried over

Ma?5O", was concentrated and purified by flash chromatography (silica gel, 40 g, UV254, PE/EA: from 100/1 to 2/1) to give the target compound (120 mg, 40 95) as a gray solid. HOM: (MANI -294.0.

2O Intermediate B13: The target compound was obtained by a method similar to that used for the preparation of Intermediate VI by replacing B1.4 with B13.2. The crude product was used in the next step without additional purification. And SM: (MANI -260.1.

Intermediate compound B14: 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)uoxazolidin-2-one and -y- ozhry Z: o it o g ber h o-h - Y SCHI z KE A vi -Sh-- rya Ku y

IN Weight 24 Shchi M 9 M 41 A 3-(5-Bromopyridin-2-yl)uoxazolidin-2-one (814.1): a mixture of 2,5-dibromopyridine (1.0 g, 4.21 mmol), pyrrolidine -2-one (1.1 g, 12.7 mmol), K2CO3 (1.16 g, 8.42 mmol), Si! (40 mg, 0.21 mmol),

M1,M1,M2,M2-tetramethylethane-1,2-diamine (50 mg, 0.42 mmol) and dioxane (10 ml) were stirred at 1102C for 12 h. Water (30 ml) was added to the mixture, EA was extracted (20 ml x 3), the extracts were washed with water (25 ml x 3) and saline (20 ml x 3), dried over

Ma?5O", was concentrated and purified by flash chromatography (silica gel, 40 g, UV254, PE/EA: from 100M to 2MI) to give the target compound (380 mg, 37 90) as a gray solid

From the color G/CM: |MaNI-244.9.

Intermediate B14: The target compound was obtained by a method similar to that used for the preparation of Intermediate VI by replacing B1.4 with B14.1. AND! CM5:

IMANI-291.0.

Intermediate compound B15: 3-(2--"methylsulfonyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and , I

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3-Bromo-5-(2-bromomethoxy)pyridine (815.1): a mixture of 5-bromopyridine-3-ol (500 mg, 2.87 mmol), 1,2-dibromoethane (810 mg, 4.31 mmol), Kg2CO3 (792 mg, 5.74 mmol) and OME (10 mL) were stirred at room temperature for 12 h. The mixture was diluted with 10 ml of water, extracted with EA (10 ml x 3), the organic layers were washed with water (25 ml x 3) and saline (20 ml x 3), dried over Mag50", concentrated and purified by flash chromatography (silica gel, 40 g,

PE/EA- from 100/1 to 2/1) to obtain the target compound (200 mg, 20 95) in the form of a gray solid. GSM5: (MANI -279.9.

3-Bromo-5-(2-(methylsulfonyl)ethoxy)pyridine (815.2): mixture B15.1 (200 mg, 0.71 mmol),

MaozosinH (126 mg, 1.07 mmol) and OM 5 O (2 mL) were stirred at room temperature overnight. Water (10 ml) was added to the mixture, EA was extracted (10 ml x 3), the extracts were washed with water (25 ml x 3) and saline (20 ml x 3), dried over Mag"50O5", concentrated and purified by flash chromatography (silica gel, 40 g, PE/EA: 100/1 to 2/1) to give the target compound (150 mg, 61 90) as a gray solid. GSM5:

IMANI-280.0.

Intermediate B15: The target compound was prepared by a method similar to that used to prepare Intermediate VI by replacing B1.4 with B15.2. ! CM5:

IMANI-328,2.

Intermediate compound B16: 6-(2-oxopiperazin-1-yl)pyridin-3-ylboronic acid shk on

From sit -Vg o tr in.

Although 1 ortho» o h ts Ty M I 7 -- g syu -0-x ne shi ke M

Watt VTM YAM and i

Acid dov NM i viv viv viv viv viv tert-butyl-4-(5-bromopyridin-2-yl)-3-oxopiperazine-i-carboxylate (816.1): a mixture of -2,5-dibromopyridine (1.0 g, 4.21 mmol), pyrrolidin-2-one (2.54 g, 12.7 mmol), K2CO3 (1.16 g, 8.42 mmol), Sii (40 mg, 0.21 mmol), M1, M1, M2, M2-tetramethylethane-1,2-diamine (92 mg, 0.63 mmol) and

From dioxane (10 ml) was stirred at 1102C for 12 hours. Water (30 ml) was added to the mixture, EA was extracted (20 ml x 3), the organic layers were washed with water (25 ml x 3) and saline (20 ml x 3), dried over Mag25O05, concentrated and purified by flash chromatography (silica gel , 40 g, PE/EA: from 100/1 to 2/1) to obtain the target compound (750 mg, 50 95) in the form of a gray solid. HOM: (MANI -356.1. tert-butyl-3-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl) )piperazine-1-carboxylate (816.2): The target compound was obtained by a method similar to that used for the preparation of Intermediate Bi, by replacing B1.4 with B16.1. The crude product was used in the next step without further purification. I SM: (M '-NO: -404.,0.

Intermediate B16b: A mixture of B16.2 (100 mg, 0.31 mmol) in HCl/dioxane (0.6 mL) was stirred at room temperature for 2 h. Water (30 ml) was added to the mixture, EA was extracted (20 ml x 3), the extracts were washed with water (25 ml x 3) and saline (20 ml x 3), dried over NaCl, concentrated and purified by preparative HPLC to give of the target compound (50 mg, 40 95) as a gray solid. AND! CM5:

IMANI-222.2.

Intermediate compound B17: M-4-(2-hydroxyethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide p tire

BE Ve go

Ah r V! dO I M 7, oh550 Ohko ochono a AN IZ

MN ne i no vi Vi? 4-Bromo-M-(2-hydroxyethyl)/benzenesulfonamide (817.1): To a solution of 4-bromobenzene-1-sulfonyl chloride (2.0 g, 7.9 mmol) in OCM (30 mL) was added 2-aminoethanol (4 .8 g, 79 mmol) and

BIREA (2.0 g, 15.8 mmol) at 0 C, then the reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with EN (10 ml x 2), dried in vacuo to give the target compound (1.8 g, yield 90 95) as a white solid. EM: (MANI: -281.9.

Intermediate B17: The target compound was prepared by a method similar to that used to prepare Intermediate VI by replacing B1.4 with B17.1. I CM5:

IMANI-328.0.

Intermediate compound B18: 6-(2-methylpyrrolidin-1-yl)pyridin-3-ylboronic acid. with i EVERYTHING and "y Conditions. 3 Her. and ak MY SHY - VV IN

ELSm d We don't KI rik o! OM, Mch

Viva viv 5B-Bromo-2-(2-methylpyrrolidine-1-ylylpyridine (818.1): To a solution of 5-bromo-2-fluoropyridine (5.71 mmol, 1 g) in Hg2O (3 mL) was added 2-methylpyrrolidine hydrochloride ( 8.57 mmol, 0.73 g) and K»CO3 (11.43 mmol, 1.58 g), and the mixture was stirred at 11523 for 3 h. The mixture was concentrated and purified by flash chromatography (reverse phase, C-18, 10 mmol of МНАНнСО3:СН3ОНН--0-80 95,

UF254 and UF2g14) to obtain the target compound (900 mg, 65 95) in the form of a yellow oil. ! CM5:

IMANI-241,1.

Intermediate compound B18: To a solution of B18.1 (0.622 mmol, 150 mg), bis(pinacolato)diboron (158 mg, 0.622 mmol) and COAc (1.24 mmol, 121 mg) in dioxane (6 mL) was added Ra(arros " (0.062 mmol, 45.5 mg). The reaction mixture was heated at 902C for 2 hours in an M"2 atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was used in the next stage without additional purification. SM: IMANI:-207 ,2.

Intermediate compound B19: (4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)/pyridin-2-yl)(pyrrolidin-1-yl)umethanone ot echya take A and Щ Х nt

I am in ---ouyu m r -O hr M M

My a (i B; g son y 4 m, da iz, di 5B-Bromo-4-methylpicolinoyl chloride (819.1): a mixture of 5-bromo-4-methylpicolinic acid (5.6 mmol, 1.2 g) and 10 ml of thionyl chloride was stirred at 902C for 2 hours. After cooling to room temperature, the mixture was concentrated to obtain the target compound (1

Zo g, 77 Cho) in the form of a yellow solid substance. HOM: (MANI: -236.1. (5-Bromo-4-methylpyridin-2-yl)(pyrrolidin-1-yl)umethanone (819.2): To a solution of pyrrolidine (3.21 mmol, 228 mg) in 10 ml OIREA (6.42 mmol, 829 mg) was added to OCM at 09 C. After stirring at 02 C for 10 minutes, B19.1 (2.14 mmol, 500 mg) was added portionwise to the mixture, stirred at 09 C for 20 minutes, then allowed to warm to the room

C5 temperature and stirred for another 2 h., concentrated and purified flash

chromatography (silica gel, REEA-0-409o, UV254 and UV2g80 nm) to obtain the target compound (560 mg, 97 95) in the form of a yellow solid. SM: (Ma-NI-269,1.

Intermediate compound B19: The target compound was obtained by a method similar to that used for the preparation of Intermediate compound VI, by replacing B1.4 with B19.2. ! CM5:

IMANI-317,4.

Intermediate compound B20: 4-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)upicolinamide o ! "In Z v

Veshn, Su Y v V. s te sh M

SI -M. M led the corner in the 2nd

B-bromo-M,M,4-trimethylpicolinamide (820.1): To a solution of dimethylamine hydrochloride (3.21 mmol, 262 mg) in 10 ml of OSM at 09C was added OIREA (6.424 mmol, 829 mg). The mixture was stirred at 02C for 10 minutes, B19.1 (2.141 mmol, 500 mgHg) was added in portions.

The mixture was stirred at 02C for 20 minutes, then warmed to room temperature for 2 hours, concentrated and purified by flash chromatography (silica gel, RE'EA:-:0-50 95,

UV254 and UV280 nm) to give the target compound (560 mg, 97 95) as a yellow solid. SM: (MANI -243.1.

Intermediate B20: The target compound was obtained by a method similar to that used for the preparation of Intermediate VI by replacing B1.4 with B20.1. And CM5:

IMANI-291,2.

Intermediate compound B21: 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethanol / / / и / / -o j Me 0 O-e- shk topic 0-00 АЙ У ОВ

Shchy Ge) x rey vru u o I nal Shch zl I you

XX in the branches 1-(2-(tert-butyldimethylsilyl)oxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) )-1H-pyrazole (821.1): To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.35 mmol) in SNISM (5 mL) was added C52CO3 (800 mg, 2.102 mmol) and (2-bromomethoxy)(tert-butyl)dimethylsilane (50 mg, 1.892 mmol). The mixture was stirred at 902C overnight, concentrated and purified by flash chromatography (silica gel, PE'EA-0-15 956, UV254 and UV2g80) to give the target compound (300 mg, 77 90) as a yellow oil. And SM: (MANI -381.7.

Intermediate compound B21: TVAE was added to a solution of B21.1 (300 mg, 0.79 mmol) in TNE (6 mL)

Zo (412 mg, 1.58 mmol). The mixture was stirred at 302C for 3 hours, concentrated under reduced pressure to give the target compound (100 mg, 48 95) as a yellow oil. SM:

IMANI-267.

Intermediate compound b22: 1-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,9,2-dioxaborolan-2-yl)-1H-pyrazole and ema

Hv ma ak day o i in M

And in M

Movia, school

NMA, U o x vg2

To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.68 mmol, 150 mg) in SNISM (5 ml) was added 1-bromo-2-methoxyethane (0.95 mmol, 130.5 mg). The mixture was stirred at 902C for 6 hours, concentrated under reduced pressure, purified by flash chromatography (silica gel, REEA-0-209o, UV254 and UV2g80 nm) to obtain the target compound (100 mg, 52 95) in the form of a yellow solid. SM: (Ma-NI-281.5.

Intermediate compound in 23: 3-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,9,2-dioxaborolan-2-yl)pyridine in y os di M m o ry in B .o and i nin | | -080--- Ah I ko r

EM zam AV M Deu M o Ks 23 23.2 dz 5B-Bromo-3-methyl-2-(methylthio)pyridine (823.1): a mixture of 5-bromo-2-fluoro-3-methylpyridine (1 g, 5.26 mmol) , CHzZMa (479 mg, 6.84 mmol) in OME (10 ml) was stirred for 3.5 h. at 02C in an M2 atmosphere. The mixture was diluted with 50 ml of water, extracted with ethyl acetate (50 ml x 3). The combined organic layers were successively washed with 50 ml of water and saline solution (50 ml), dried over Mag25O5, and concentrated to give the target compound (1.1 g, 9595) as a white solid. I SM: (MANI -218. 5-Bromo-3-methyl-2-(methylsulfonyl)pyridine (823.2): To the mixture B23.1 (1.1 g, 5 mmol) in OSM (11 ml) was added t-SRBA (2.58 g, 15 mmol) at 0 "C. The mixture was stirred overnight at room temperature, then quenched with an aqueous solution of 2 mol/L Mahon (50 ml), extracted with ethyl acetate (50 ml x 2). The combined organic layers washed sequentially with 50 ml of HO and saline solution (50 ml), dried over Mag2505, concentrated to obtain the target compound (1.2 g, 96 95) in the form of a white solid. I SM: (MANI -249.9.

Intermediate B23: The target compound was prepared by a method similar to that used to prepare Intermediate VI by replacing B1.4 with B23.2. ! CM5:

IM-ANI-216.1 (tb: corresponding boronic acid).

Intermediate compound B24: (5-methyl-6-morpholinopyridin-3-yl)/boronic acid son y. "VE Y A son, zu v dv- zrob ten i - -- so chi a an - mk shi y

Oh 7 Zm tsi Y U i g chok g vot i N oo

ZA 24 vza 4-(5-bromo-3-methylpyridin-2-ylylmorpholine (824.1): a mixture of 5-bromo-2-fluoro-3-methylpyridine (2.5 g, 13.2 mmol), morpholine (3.4 g, 39.6 mmol), K2CO3 (5.5 g, 39.6 mmol) in 40 ml of OM5O was heated to 1202C and stirred for 16 h. The mixture was cooled to room temperature.

200 ml of water was added, extracted with ethyl acetate (150 ml x 3). The combined organic layers were washed with 150 ml of water and saline solution (150 ml), dried over Ma»5Ox,

Zo was concentrated to give the target compound (1.8 g, 53 95) as a white solid. HOM: (MANI -257.0.

Intermediate 824: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by substituting B18.1 for B24.1. And CM5:

IMANI-223.4.

Intermediate compound in B25: 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)upropan-2-ol and the lines of FI and vision of VI gly v.r

According to the formula (9; 25 25 2-(5-Bromopyridin-2-yl)upropan-2-ol (825.1): To the mixture of 1-(5-bromopyridin- of 2-yl)ethanone (400 mg, 2 mmol) in 8 ml of TNE was added ml of CH3MoOoVg (1 mol/l) at -152С in an atmosphere of Me". The mixture was stirred for 5 h at 25 °C, quenched with saturated MNACI ( 30 ml) and stirred for 1 hour, extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with 50 ml of water and 50 ml of brine, dried over Ma»5O»4, concentrated. The residue was purified on silica gel (PE /EA-10:1) to obtain the target compound (180 mg, 42 95) in the form of a colorless oil." 1H), 7.82 (dd, 1H), 8.58 (d, 1H).

Intermediate B25: The target compound was prepared by a method similar to that used to prepare Intermediate VI by substituting B1.4 for B25.1. And CM5:

IM-ANI-264.2.

Intermediate compound v2g6: 4-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in o x Ve Z v.

A Ve gu o, uv F) Su 9 ri MT pi i nina p past

ET about She;

II of the 2nd c

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound B23, by replacing 5-bromo-2-fluoro-3-methylpyridine with 5-bromo-2-fluoro-4-methylpyridine. SM: (MANI -298.1.

Intermediate compound v27: 2-methyl-6-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and o. / в вт хы Велк Вед» А ВЕ в b С ТТ 9 Й r вт В272 Intermediate compound В27

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound B23, by replacing 5-bromo-2-fluoro-3-methylpyridine with 3-bromo-6b-fluoro-2-methylpyridine. SM: (MANI -298.1.

Intermediate compound v28: 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)upiperazin-2-one and V or

Your cake is magnificently pr po p i s ep i M

Z A ET and I -a ki NM... r

NM. and that's it! 9 included 4-(5-Bromopyridin-2-yl)piperazin-2-one (828.1): a mixture of 5-bromo-2-fluoropyridine (1 g, 5.68 mmol), piperazin-2-one (1.7 g, 17 mmol), K2CO3 (2.35 g, 17 mmol) in 20 ml of OM5O was heated at 1202C and stirred for 16 h. The mixture was cooled to room temperature, 80 ml of water was added, extracted with ethyl acetate (60 ml x 3), the combined organic layer was washed with 100 ml of water and 100 ml of brine, dried over Na»5O», concentrated, the residue was purified on silica gel (OSM /Meon-10:1) to give the target compound (250 mg, 17 Ov) as a white solid. And SM: (M'NI-255.9.

20 Intermediate B28: The target compound was obtained by a method similar to that used for the preparation of Intermediate VI by replacing B1.4 with B28.1. And CM5:

IMANI-304,4.

Intermediate 829: 4,4,5,5-Tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane

: a -

In p i" what ra z se vo

No" spring in ve in A rya A I raka and ! she: O Intermediate vB2gzl 28.2 B29.5 snoluka B29

Methyl(m-tolyl)usulfan (829.1): To a mixture of 3-methylbenzenethiol (2 g, 16 mmol) in 20 mL of OME was added Mann (0.96 g, 24 mmol) at 0 °C. The mixture was stirred for 30 min at 25 20.

After cooling to 02C, CH2 (22.7 g, 160 mmol) was added dropwise. The mixture was stirred for 2 hours. at room temperature, diluted with 100 ml of water, extracted with ethyl acetate (60 ml x 3). The combined organic layers were washed with saline solution (50 ml x 1), dried over Mag5O:, and concentrated. The residue was purified by silica gel (eluting with PE/EA-100:0) to give the target compound (1.3 g, 59965) as a colorless oil. The crude product was used in the next stage without further purification. (4-Bromo-3-methylphenyl)(methyl)sulfan (829.2): a mixture of B29.1 (1.3 g, 9.4 mmol) in 30 ml of ASON was cooled to 0 °C, Bg»o (1, 5 g, 9.42 mmol), and the mixture was stirred for 3 hours at 25 °C. The mixture was concentrated and purified on silica gel (eluting with PE) to give the title compound (1.7 g, 85965) as a colorless oil. The crude product was used in the next step without additional purification. 1-Bromo-2-methyl-4-(methylsulfonyl)benzene (829.4): To a mixture of B29.2 (1.7 g, 7.83 mmol) in 20 mL of OSM was added t-SRBA (4.04 g, 23, 5 mmol) at 0 °C. The mixture was stirred for 16 h at 25 °C, quenched with 40 ml of water, then extracted with OSM (50 ml x 2), the combined organic layers were washed with saline (50 ml), dried over Mag25O4 , concentrated. The residue was purified on silica gel (eluting with PE/EA-7:3) to give the target compound (1.3 g, 66 95) as a white solid. "H NMR (400 MHz, SOSIz) b ppt 2.50 (s, ZN), 3.05 (s,

ЗН), 7.62 (dd, 2.3 Hz, 1Н), 7.74 (d, 1Н), 7.80 (d, 1Н). AND SM: NAMES: -2491.

Intermediate 829: The target compound was prepared by a method similar to that used to prepare Intermediate VI by replacing B1.4 with B29.4. The crude product was used in the next stage without further purification. And SM: (MANI -314.0.

Intermediate compound B30: (6-(3-(dimethylamino)-33-oxopropyl)pyridin-3-yl)/boronic acid

BE t, V s VG tyu what J sho i --sh y . --- | And I study

SYA i Ve SA Te i v a Go) 301 ОЙ z slshe vysh ano - Metu M i M sh-eya M - o M na hei o o o o 304 30.3 (E)-ethyl. 3-(5-Bromopyridin-2-yl acrylate (830.1): a mixture of 5-bromopicolinaldehyde (0.93 g, 5 mmol), ethyl 2-bromoacetate (1.25 g, 7.5 mmol), Manso's (1 .26 g, 15 mmol), PP3 (1.83 g, 7 mmol), water (10 ml) in 5 ml of ethyl acetate was stirred for 16 h at 252C in an atmosphere

From M". The mixture was diluted with water (30 ml), extracted with ethyl acetate (40 ml x 2), the combined organic layers were washed with water (40 ml) and brine (40 ml), dried over Ma250Oa, and concentrated. The residue was purified on silica gel (PE/EA-6:1) to give the target compound (1.1 g, 85 95) as a white solid. And SM: (MANI -256.0.

Ethyl 3-(5-bromopyridin-2-yl/upropanoate (830.2): A mixture of BZ3O.1 (1 g, 3.9 mmol), SiC (406 mg, 4.1 mmol) in 20 mL Meon was cooled to 0 " C, MavBna (1.18 g, 31.2 mmol) was added in portions, the mixture was stirred for 5 h at 09 C in a Mg atmosphere. The mixture was filtered, concentrated to dryness. The residue was purified on silica gel (PE/EA: from 0 to 20 95) with obtaining the target compound (600 mg, 60 95) in the form of a colorless oil. I SM: (MANI -260.0. 3-(5-Bromopyridin-2-yl)upropanoic acid (830.4): a mixture of ethyl B30.2 (600 mg, 2.32 mmol),

Mahon (928 mg, 23.2 mmol) in a mixed solution of TNE (14 mL), water (7/7 mL), and MeOH (7 mL) was stirred for 2 h. at 40 "b. The mixture was acidified to pH--2-3 using In. HCI, then concentrated. The residue was diluted with water (30 ml), extracted with OSM/MeOn (10/1) (40 ml x 4), dried over Ma »505, concentrated to obtain the target compound (375 mg, 70 95) in the form of a white solid. (830.4): a mixture of B30.4 (400 mg, 1.74 mmol), dimethylamine hydrochloride (570 mg, 6.96 mmol), NATIi (992 mg, 2.61 mmol), OIEA (1.79 g, 13, 92 mmol) and OSM (20 ml) were stirred for 5 h at 252C in an atmosphere of M". The mixture was diluted with water (30 ml), extracted with EA (30 ml x 3), the combined organic fractions were washed with water (40 ml) and saline solution (40 ml), dried over Mag5O", concentrated. The residue was purified by preparative HPLC to obtain the target compound (260 mg, 58 95) in the form of a white solid. I SM: |(MaNI-259.0.

Intermediate B30: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by substituting B18.1 for B30.4. The crude product was used in the next step without additional purification. And SM: (MeNI: -305.4 for pinacol ester of boronic acid; 223.1 for boronic acid.

Intermediate compound B31: 2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylomorpholine and xx. VG la. B 3 mg of 4-(5-Bromopyridin-2-yl)-2,6-dimethylmorpholine (831.1): 5-bromo-2-fluoropyridine (3.0 g, 20 mmol) in DMSO was added to a solution of 2,6-dimethylmorpholine (6.9 g, 60 mmol) and K»CO3 (8.3 g, 60 mmol) in 10 ml of OH 5 O. The reaction mixture was heated at 1302C for 16 h. The reaction mixture was cooled to room temperature and added 100 ml of H2O followed by extraction

EUAs (2x100 ml). The organic layers were washed successively with brine (100 ml), dried over Na»5O»5 and concentrated under reduced pressure to give the target compound (4.38 g, 81 95) as a yellow solid. And CM5: |MeNI-273.0.

Intermediate compound B31: The target compound was obtained by a method similar to that used for the preparation of Intermediate compound VI, by replacing B1.4 with B31.1. And CM5:

IMANI-319.0.

Intermediate compound B32: 4,4,5,5-tetramethyl-2-(4-(-2--"methylsulfonyl)ethoxy)phenyl)-1,3,2- dioxaborolane

Vi sl tr z vi V --kh- tru i ri 4 still more. Oh, you fools

He is V. Well, yes

And according to Iv. and t Sh Z iy chu yiv vZ2 32.3

Zo 1-Bromo-4-(2-bromomethoxy)benzene (832.1): a mixture of 4-bromophenol (4.3 g, 25 mmol), 4- bromophenol (12.7 g, 67.5 mmol), Mahon (1, 6 g, 40 mmol) in HO (20 ml) was heated under reflux for 11 h. UOSM (50 ml) was added. The organic phase was separated and concentrated to give the target compound (4.2 g, 60 95). The crude product was used in the next stage without further purification. (2-(4-Bromophenoxy)ethyl)(methyl)sulfan (832.2): A mixture of B32.1 (4.3 g, 25 mmol), CH35Ma (6.12 g, 45 mmol) in OME (50 mL) was heated at 902C for 18 hours. OSM (50 mL) and water (100 mL) were added. The organic phase was separated and concentrated to give the target compound (2.9 g, 80 95). The crude product was used in the next stage without further purification. 1-Bromo-4-(2-(methylsulfonyl)ethoxy)benzene (832.4): a mixture of B32.2 (2.9 g, 12 mmol), t-SRBA (7.28 g, 36 mmol) in OSM (50 ml ) was stirred at room temperature for 18 h.

OSM (50 mL) and water (100 mL) were added. The organic phase was separated and concentrated. The residue was purified by chromatography on silica gel, eluting with a mixture of PE/EMAcS-1/1, to obtain the target compound (2.7 g, 80 95) in the form of a pale yellow solid. The crude product was used in the next step without additional purification.

Intermediate B32: The target compound was prepared by a method similar to that used to prepare Intermediate VI by substituting B1.4 for 832.4. AND! CM5:

IMANIG-327,2.

Intermediate compound B33: 2-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

MV dyan and M that du ut, Bo vya ov 833.1

H osi rya -Vg bori Vs M

Yi Yi z

33.2 33 5-Bromo-2-vinylpyridine (833.1): RA(PPIz)4" (500 mg, 0.4 mmol) was added to a stirred suspension of 2,5- dibromopyridine (5 g, 21 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.6 g, 23 mmol) in a mixture of 1,4-dioxane (40 ml) and saturated sodium carbonate solution (12 ml).

The mixture was stirred at 1002C for 16 hours. in a closed test tube under a nitrogen atmosphere. The mixture was diluted with dichloromethane (200 mL) and washed with water (100 mL). The organic layer was separated, dried over Ma»5O»4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel column, dichloromethane in heptane 20/80 to 80/20) to give the target compound (2.9 g, 77 95). The crude product was used in the next stage without further purification. I SM: (MANI -186.0. 5-Bromo-2-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridine (833.2): B33.1 (500 mg, 2.72 mmol) was added to a solution of 3,3-difluoropyrrolidine (930 mg, 8.16 mmol) in acetic acid (3 mL), and the mixture was stirred at 1002C for 18 h. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (50 mL). the layer was dried over anhydrous sodium sulfate, concentrated, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate-10:1, chloroform:methanol--10:1) to give the target compound (500 mg, 68 90).The crude product was used at the next stage without additional purification. I SM: (MANI -293.0.

Intermediate B33: The target compound was prepared by a method similar to that used to prepare Intermediate VI by replacing B1.4 with 833.2. ! CM5:

IMNII-257.2 (MH:" of boronic acid).

Zo Intermediate compound B34: (6-(2-(dimethylamino)ethyl)pyridin-3-yl)/boronic acid on g | -IN. shkh II Met, SG on

Would X V Zx zm! Preparation of 2-(5-Bromopyridin-2-yl)-M,M-dimethylethanamine (834.1): A solution of 2.0 M dimethylamine (27 mL, 54 mmol) in TNE was added to a solution of 5-bromo-2-vinylpyridine (1.0 g, 5.4 mmol) in acetic acid (7 mL). The mixture was stirred at 802C overnight and at 902C for two days, then quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate-10:1, chloroform : methanol-10: 1) to give the target compound (900 mg, 60 95). The crude product was used in the next stage without further purification. And SM: (MANI -231.1.

Intermediate B34: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by substituting B18.1 for B34.1. And CM5:

IMANI-195.2.

Intermediate compound 35: 2-(methoxymethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,9,2-dioxaborolan-2-yl)pyridine -- Kofko;

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Methyl 5-bromo-3-methylpicolinate (835.1): To a solution of 5-bromo-3-methylpicolinic acid (500 mg, 2.31 mmol) in MeOH (10 mL) was added 5OCI" (275 mg, 23.1 mmol) at room temperature.

Then the reaction mixture was stirred at 902C for 4 hours. The solvent was removed to give the target compound (500 mg, 94 95) as an off-white solid.

The crude product was used in the next stage without further purification. ISM5:

IMANI-232.0. (5-Bromo-3-methylpyridin-2-ilumethanol (835.2): To a solution of B35.1 (500 mg, 2.17 mmol) in

Meon (15 mL) was added Mavna (826 mg, 21.7 mmol) at room temperature. Then the reaction mixture was stirred at 902C for 2 hours. The solvent was removed. The residue was dissolved in

EAs (20 mL) and washed with water (15 mL). The organic phase was concentrated to give the target compound (300 mg, 68 90) as a pale yellow oil. The crude product was used in the next stage without further purification. I SM: (MANI -204 2.5-Bromo-2-(methoxymethyl)-3-methylpyridine (835.4): Methyl iodide (254 mg, 1.79 mmol) was added to a stirred suspension of 835.2 (300 mg, 1.49 mmol) and Man (89 mg, 2.23 mmol) in

TNE (8 ml). The reaction mixture was stirred at room temperature for 1 hour. They added

OSM (20 ml) and water (15 ml). The organic phase was separated and concentrated. The residue was purified by preparative TS (PE/EUAs-2/1) to obtain the target compound (310 mg, 96 95) in the form of a solid. The crude product was used in the next step without additional purification. And SM: NAMES -218.1.

Intermediate B35: The target compound was prepared by a method similar to that used to prepare Intermediate VI by substituting B1.4 for 835.4. And CM5:

IMANI-264.0.

Intermediate 836: 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)ethyl)piperazin-2-one oct )

The target compound was obtained by a method similar to that used for the preparation

From Intermediate compound BZ33, by replacing 3,3-difluoropyrrolidine with piperazin-2-one. GSM5:

IMANI-332.0.

Intermediate compound B37: 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1,4-diazepan-1-carbaldehyde c

I am dry with my son

EM is the country of the VU

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound BZ31, by replacing 2,6-dimethylmorpholine with 1-formyl-1,4-diazepan-b-ylium.

SM: (MANI -332.4.

Intermediate 838: 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)ethyl)piperazine-1-carbaldehyde wasp times, see "M sons of Mokh pov tyurrya and A. and I

NO din NI TO Y PV t o V

In Y and In Her OM about visa vZV.2 vza

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound B33, by replacing 3,3-difluoropyrrolidine with piperazine-1-carbaldehyde.

SM: (MANI -346.4.

Intermediate 839: 2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)upiperazin-1-yl)ethanol

And t in in

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M: I-MN S i sus IY iy

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ZO no vza

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound BZ3Z1 by replacing 2,6-dimethylmorpholine with 2-(piperazin-1-yl)ethanol.

SM: (MANI -334.,2.

Intermediate B40: (6-(Dimethylcarbamoyl)pyridin-3-yl)/boronic acid

GIVE Du o M - nzh--- A - - - 5 nya schi o o o o

AL Ai 5-Bromo-M, M-dimethylpicolinamide (840.1): Oxalyl chloride (5 ml) was added to a solution of 5-bromopicolinic acid (1.5 g, 7.42 mmol) in OSM (15 ml) at 02С. The reaction mixture was stirred at 402C for 1 hour, concentrated under reduced pressure. The residue was diluted with OSM (20 mL) and OIREA (1.5 g) and dimethylamine (600 mg) were added sequentially. The mixture was stirred for 1 h, concentrated, and the residue was purified by flash chromatography using PE/EA 5:11 to give the target compound (700 mg, 49 95). The crude product was used in the next step without additional purification. And SM: (MANI -231.1.

Intermediate 840: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by substituting B18.1 for B40.1. The crude product was used in the next step without additional purification. And SM: (MANI -195.4.

Intermediate compound Ba1: Pyrrolidin-1-yl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)upyridin-2-yl)umethanone

Be Vg - V y ; them -- sa yu MI KY TO

(5-Bromopyridin-2-yl)(pyrrolidin-1-yl)umethanone (841.1): the target compound was obtained by a method similar to that used for obtaining Intermediate B40.1 by replacing dimethylamine with pyrrolidine.

Intermediate compound B41: To solution B41.1 (70 mg), bis(pinacolato)diboron (77 mg, 0.305

2 mmol) and COAc (59 mg, 0.604 mmol) in dioxane (2 ml) was added Pa(arrosi) (20 mg). The reaction mixture was heated at 1102C for 2 hours under an atmosphere of M". After cooling to room temperature, the mixture was filtered, the filtrate used at the next stage without additional purification. I CM: IM--NI-303.2 (for boronic acid, I CM: MANI -221.2.)

Intermediate B42: M-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

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M - yo M shk shi o o o

B42?

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound B41, by replacing dimethylamine with hexamethylenetetramine. The crude product was used in the next step without additional purification. And SM: (M'-NI-181,1.

Intermediate B43: M-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamidon le VE pt VE : no | 7 - - --yahzh She M -- - -- ь- - M ! lol

I r tm o o o vase vase

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound B41, by replacing dimethylamine with ethanamine. The crude product was used in the next step without additional purification.

Intermediate 844: M-(2-(Dimethylamino)ethyl)-M-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamidon

VG re Z and i

SCHI --o o : - - - - 26- o. t! M 2 M i

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Iva | wow

The target compound was obtained by a method similar to that used for the preparation

Intermediate compound B41, by replacing dimethylamine M1,M1,M2-trimethylethane-1,2-diamine.

The crude product was used in the next step without additional purification. And CM5:

IMANI-252.2.

Intermediate compound B45: (5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)/boronic acid

Ve M Ve". rya re tive

Me i nom: M zm vil Va; 2-(5-Bromopyridin-3-yl)-4,4-dimethyl-4,5-dihydrooxazole (845.1): Zinc chloride (73.7 mg, 0.55 mmol) was placed in a 100 mL round-bottom flask, melted three times under high pressure and allowed to cool to ambient temperature in an M atmosphere, after which a solution of 5-bromonicotinonitrile (1 g, 5.5 mmol) and 2-amino-2-methylpropan-1-ol (513 mg, 5.8 mmol) was added ) in dry chlorobenzene (15 ml). The resulting mixture was remelted for 48 hours. in the M2g atmosphere. Volatiles were removed in vacuo and water (20 mL) was added. The aqueous layer was extracted with OSM (3x10 ml), and the combined organic extract was washed with water, saline solution, and dried over Mag50O. and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (PE/EA: 100/1 to 3/1) to give the target compound (1 g, 71 90) as a white solid. And SM: (MANI: -257.1.

zo Intermediate 845: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by substituting B18.1 for B45.1. And CM5:

IMANI-221,2.

Intermediate 846: (6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)/boronic acid

Veoott ih Ve nku shk She Won i how rOonoh us he i 8 M. dtan And day, but I i o

M: We washed, 9 m of them were dissolved in water. of 5-bromopicolinic acid (1.2 g, b mmol) at ambient temperature in an atmosphere of M". The resulting mixture was heated under reflux for 2 hours, and the volatiles were removed in vacuo. The crude acid chloride was dissolved in dry

OSM (20 mL), and the solution was slowly added at 02C to a solution of 2-amino-2-methylpropan-1-ol (1.6 g, 18 mmol) in OSM (5 mL). After stirring for 48 hours. at ambient temperature, the solvents were removed in vacuo and the crude product was purified by flash chromatography on silica gel (PE/EA: 100/1 to 5/1) to give the target compound (1.5 g, 93 95) as a white solid . I SM: (MANI -273.1. 2-(5-Bromopyridin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (846.2): solution B46.1 (1 g, 3.7 mmol) in thionyl chloride (967 mmol, 5 ml) was stirred for 12 h at room temperature.

The solvent was removed in vacuo and dry OSM (20 mL) was added. The separated organic layer was washed with 2N. with an aqueous Mahon solution (2x25 ml), dried over Md5O»5 and concentrated in a vacuum. The crude product was purified by flash chromatography on silica gel (PE/EA: 100/1 to 1/1) to give the target compound (850 mg, 91 95) as a white solid. And CM5:

IMANI-257.0.

Intermediate 846: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by replacing B18.1 with B46.2). And CM5:

IMANI-221,1.

Intermediate B47: (5-(Methoxymethyl)-6-methylpyridin-3-yl/boronic acid

On 1 pln. i VE toru V ol V. pt u zv not ri o Her her o ri T on

47.2 47 (5-Bromo-2-methylpyridine-3-ilumethanol (847.1): To a solution of ethyl 5-bromo-2-methylnicotinate (1.0 g, 411 mmol) in MeOH (15 ml ) sodium borohydride (500 mg, 12.5 mmol) was added in portions at 0 "C. After 1 h, the reaction was stopped by adding water (10 ml). The reaction mixture was then extracted with OSM (3x10 ml). The extracts were combined, dried over Mag5O ", concentrated and purified by column chromatography on silica gel (PE/EA: from 100/1 to 5/1) to obtain the target compound (650 mg, 79 95) in the form of a white solid. I SM: (MANI -201.9 5-Bromo-3-(methoxymethyl)-2-methylpyridine (847.2): To mixture B47.1 (200 mg, 1.0 mmol) in TNE

Man (60 wt. 90, 48 mg, 1.2 mmol) was slowly added to Zo (10 ml) at 02C. The mixture was stirred at 02C for 30 minutes, then SnNvzi (213 mg, 1.5 mmol) was added dropwise. The reaction mixture was stirred at 02C for another 2 hours, quenched with water (5 ml), extracted with EA (10 ml x 3), the combined extracts were washed with brine (10 ml x 3), dried over Na»5O», concentrated and was purified by preparative TI C (silica gel, UF254, PE/EA-5/1) to obtain the target compound (100 mg, 70 90) in the form of a clear oil. CM: MANI -217.9.

Intermediate 847: The target compound was prepared by a method similar to that used to prepare Intermediate B18 by replacing B18.1 with B47.2. | CM5:

IMANG-182.2.

Intermediate compound C1: 8-bromo-M-(5-fluorobenzofuran-4-yl)umethyl)-(1,2,4|griazolo|4,3-c|Ipyrimidin-5-amine

B dya, see NM. Mov, city of MN KhG

COCOA kA Hn; 5-5 5 shows that the sieve is obtained with (5-Fluorobenzofuran-4-yl)uhexamethylenetetramine (C1.1): To a solution of 5-fluoro-benzofuran-4-carbonitrile (A1.4) (1 g, 6.2 mmol) in MeOnH (15 mL) and MNAOH (2 mL) was added Raney's Me (500 mg) under M2 atmosphere. The resulting suspension was degassed under vacuum and filled with He through a balloon.

Then the reaction mixture was stirred at room temperature under a H2 balloon overnight, filtered through a layer of Celite. The filtrate was concentrated and purified by flash chromatography (OSM-OSM/Meon-10/1) to give the target compound (900 mg, 88 95) in the form of a yellow oil.

CM: (MANI -166. 8-Bromo-M-(5-fluorobenzofuran-4-ylylmethyl)-P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine (C1): a mixture of (5-fluorobenzofuran- 4-Iluhexamethylenetetramine (C1.1) (203 mg, 1.23 mmol) and 8-bromo-5-(methylthio)-(1,2,4)griazolo|4,3-c|Ipyrimidine (3) (200 mg , 0.82 mmol) was stirred at 4020 for 12 h. After completion of the reaction, EA (15 mL) was added. The solid was filtered and washed with EA (3 mL x 3). The solid was collected to give the target compound as a white solid ( 50 mg, 17 95). And SM: (MANI -362.

Intermediate compound C2: (4-(8-bromo-(1,2,4|Hygryazolo|4,3-Hypyrimidin-5-ylamino)methyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol slov pcs EE old Me is sailing ON

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Vg Vg Vi Vg p24 seg 62.3 mae that the back panel -- я-к І І І --- И А ); AH du /

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Vg he cmMmoon "mno i

С24 С2.5 с2.8 2-Bromo-3,6-difluorobenzaldehyde (С2.1): To a solution of 2-bromo-1,4-difluorobenzene (16 g, 83 mol) in 200 ml of TNE in an M2 atmosphere at -782С HA (54 mL, 108 mmol) was added dropwise.

After stirring at -782C for 45 minutes, UOME (18.2 g, 249 mmol) was added. The mixture was stirred for another 2 hours. at -78 "C. The reaction mixture was heated to 02C and 200 ml of sat. Ma»50O4, filtered and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (silica gel, EUAsS/PE-1/30) to obtain the target compound (11 g, 60 95) in the form of a yellow solid. "H NMR (500 MHz, SOSI") b mp 7.57-7.44 (t, 2H), 10.20 (dd, 1H). 2-Bromo-3-fluoro-6-methoxybenzaldehyde (C2.2): To of a solution of 2-bromo-3,6-difluorobenzaldehyde (C2.1) (8.4 g, 38.0 mmol) in dry TNE (40 ml) and MeOnH (80 ml) was added a solution of MeOMa (2.26 g, 41, 8 mmol) in MeOH (40 mL) at 602C over a period of 30 min, and the resulting mixture was stirred at 602C for 16 h. The solvent was removed and water (100 mL) was added, and the resulting mixture was stirred at room temperature for 30 min. The solid was collected by filtration and then ground with PE/EA 10:1 to obtain the target compound in solid form

From a yellow substance (7.04 g, 80 95). "H NMR (500 MHz, SOSIz") b ppt 3.92 (s, ЗН), 6.94 (dd, 1Н), 7.41-7.24 (t, 1Н), 10.48 (s, 1Н ). SM: NAMES" -233.1. 2-Bromo-3-fluoro-6-hydroxybenzaldehyde (С2.4): To a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (С2.2) (5 g, 21.4 mol) in 100 ml of OSM in the atmosphere M" at -782C was added dropwise to VVgz (26 ml, 26 mmol, 1.0 mol/l in OSM). The solution was stirred at -782C for 30 minutes and at room temperature overnight. 100 ml of saturated MNASI was added at 02C and stirred for 20 minutes. The obtained mixture was extracted with SOHC (150 ml x 2).

The combined organic layer was washed with brine (400 mL), dried (Mag50O), filtered and concentrated in vacuo. The obtained crude product was purified by column chromatography (gradient elution with 0-50 9o EA in PE) to give the target compound (4 g, 8595) as a yellow solid: "H NMR (500 MHz, SOCI3) b mp 6.94 ( dd, 1H), 7.29 (dt, 1H), 10.43 (s, 1H), 11.78 (s, 1H).

B-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile (C2.53: solution of 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C2.4) (2.7 g, 11.6 mol) . room temperature and 150 mL of water was added. The mixture was extracted with EtOAc (200 mL x 2). The combined organic layer was washed with 200 mL of brine, dried (Mag2504), filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography (gradient elution: 0-50 9o EA in PE) to obtain the target compound (1 g, 60 95) in the form of a white solid. "H NMR (500 MHz, SOSIv) b ppt 2.91 (d, 1H), 4.55 ( dd, 1H), 4.69 (dd, 1H), 5.63 (s, 1H), 7.17-7.01 (t, 2H). 4-(Aminomethyl)-5-fluoro-2,3- dihydrobenzofuran-Z-ol (С2.6): To a solution of 5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile (С2.5) (1 g, 5.6 mol) in 20 ml of TNE was added dropwise

VNzI-TNE (22.4 ml, 22.4 mmol). The solution was stirred at 602C for 16 hours. The reaction mixture was cooled to room temperature and MeonH was carefully added. The resulting mixture was stirred for 30 minutes. The process was repeated three times. The crude product was purified by preparative HPLC to give the target compound (600 mg, 60 95) as a white solid. "H NMR (500 MHz, OM50-av) b ppt 3.71 (d, 1H), 3.89 (d, 1H), 4.28 (dd, 1H), 4.52 10. (dd, 1H) . Y yi I "17 Her 00007 Wu yuyu

M-M I That M-M

K. сС2.6 с 4А-((8-bromo-I1,2,4|griazolo|4,3-с|Ipyrimidin-5-yl)amino)methyl)-5-fluoro-2,3-dihydro-benzofuran -3-ol (C2): To a solution of 4-(aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (3) (400 mg, 1.6 mmol) in 2 ml of dichloromethane was added 4-(aminomethyl )-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2.6) (586 mg, 3.2 mmol), and the resulting suspension was stirred at 1002C for 3 h.

The mixture was purified by column chromatography (eluting with 1095 MeON in OSM) to give the target compound (105 mg, 17 95) as a white solid. And SM: MANI" -382.0.

Intermediate compound C3: 8-bromo-M-(5-fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)-methyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine

OMe verse OMe OMe and OMe about

Y and o erase OMe and I uayatnyaore re you - OSS yu

The GoOvVe ZOV has:

E E E p22 p3.4 p32 p3.3

Ome

AND; nah ki tem Y Z bchome

2-Bromo-1-fluoro-4-methoxy-3-(2-methoxyvinyl)benzene (С3.1): To a suspension of (methoxymethyl)-triphenylphosphonium (57.41 g, 0.167 mol) in dry TNE ( 250 ml) added I! NMOZ5 (1 M in TNE, 178.5 ml, 178.5 mmol) at 02C for 30 minutes. The resulting mixture was stirred at 02C for 45 minutes followed by the addition of a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (C2.2) (26.0 g, 0.11 mol) in dry TNE (100 ml) over 30 minutes. The resulting mixture was stirred at 2526 for 2.5 hours. and quenched with MNACI (200 ml) and extracted with ESO (150 ml x 2). The combined organic layer was washed with brine (150 mL x 1), dried (Ma»5O»), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluent: EtOAc in PE: C 95) to obtain the target compound in the form of a yellow solid

From the color (25.68 g, 88.2 95). "H NMR (400 MHz, SOSIz") b ppt 7.53 (d, 1H), 6.92-6.82 (t, 1H), 6.77 (dd, 1H), 5.99 (d, 1H ), 3.84 (s, ZN), 3.75 (s, ZN). 2-(2-Bromo-3-fluoro-6-methoxyphenyl)acetaldehyde (С3.2): To a solution of 2-bromo-1- fluoro-4-methoxy-3-(2-methoxyvinyl)benzene (C3.1) (25.68 g, 98.4 mmol) in TNE (200 ml) was added Zn.HC (100 ml, 300 mmol). The resulting mixture heated at 602C for 10 h, cooled to room temperature and extracted with SOCM (130 ml x 3). The combined organic layer was washed with MansSOOz solution (150 ml x 1), brine (150 ml x 1), dried (Mag25O4) , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with EtOAc in PE: 2 95 with 4 90). The crude product was triturated with

PE/EuOAcS (10:1, 30 ml) for 1 h. The solid was collected by filtration, washed with PE and dried in vacuo to give the target compound as a white solid (13.5 g, 55.5 90). "H NMR (500 MHz, SOSI3) b ppt 3.80 (s, ЗН), 3.96 (d, 2Н), 6.82 (dd, 1Н), 1.07 (dd, 1Н), 9.67 (t, 1H). 4-Bromo-5-fluoro-2-methoxy-2,3-dihydrobenzofuran (С3.4): To a solution of 2-(2-bromo-3-fluoro-6-methoxyphenyl)acetaldehyde (С3. 2) (11.5 g, 46.56 mmol) in OSM (100 ml) at -78"C was added

VViz (IM in OSM, 140 ml, 140 mmol) by drops in 30 minutes. The resulting mixture was heated to room temperature and stirred for 4 hours. The mixture was cooled to 0 C, carefully quenched with MeOH (30 mL) and stirred at 02 C for 2 h. The resulting mixture was extracted

OSM (100 ml x 3), and the combined organic layer was washed sat. MansSo»z (150 ml x 1), brine (150 ml x 1), dried (Mg25O04), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with EOAcC in 1.0 905 PE - 4.0 96) to give the target compound as a white solid (8.6 g, 75 95).

NMR NMR (500 MHz, SOSIv) b ppt 3.06 (dd, 1H), 3.43 (dd, 1H), 3.52 (s, ЗН), 5.67 (dd, 1H), 6, 70 (dd, 1H), 6.90 (t, 1H).

B-Fluoro-2-methoxy-2,3-dihydrobenzofuran-4-carbonitrile (C3.4): a mixture of 4-bromo-5-fluoro-2-methoxy-2,3-dihydrobenzofuran (C3.4) (4.0 g, 16.19 mmol), 7p(CM)" (3.8 g, 32.39 mmol),

RDAI(PPz)4 (936 mg, 0.81 mmol) in OME (35 ml) was heated at 1202C for 16 h. The reaction mixture was extracted with EIOAc (50 ml x 4). The combined organic layers were washed with ClCl (5 5 aqueous solution 30 ml x 2), brine (15 ml x 1), dried (Mag5O), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting

EOAc in 2 95 PE - 4 95) to obtain the target compound in the form of a white solid (2.0 g, 64 95). "H NMR (500 MHz, SOSI3") b ppt 3.21 (dd, 1H), 3.48 (dd, 1H), 3.53 (s, ЗН), 5.73 (dd, 1H), 7, 04-6.92 (t, 2H). (5-Fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)uhexamethylenetetramine (С3.5): a mixture of 5-fluoro-2-methoxy-2,3- dihydrobenzofuran-4-carbonitrile (С3.4) (2.0 g, 8.1 mmol), Mi Raney (0.2 g) in 7n.

MH3 in MeOn (60 mL) and MeOnH (30 mL) was purified by H»e and stirred at room temperature under an atmosphere of He for 30 minutes. The reaction mixture was filtered through Celite and washed

Meon (100 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, eluting with EtOAc in 10 95 PE «- 40 90; then in.

From 10 96 - 15 95) to obtain the target compound in the form of a yellow oil (1.85 g, 90 95). "H NMR (500

MHz, SOSIzv) b rrt 3.07 (d, 1H), 3.46 (dd, 1H), 3.55-3.48 (t, ЗН), 3.81 (d, 2H), 5.65 ( dd, 1H), 6.67 (dd, 1H), 6.84 (t, 13). SM: MANI" -198.2.

NOT

Sk Po,

In o z z SHI SHI | In nya Gchsche i

And no and OME KI

M-m zd m-ki OMe

With c3.5 c3 8-Bromo-M-(5-fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)methyl)-P1,2,4Hygriazoloi|4,3- c|Ipyrimidin-5-amine (C3): a mixture of (5-fluoro-2-methoxy-2,3-dihydrobenzo-furan-4-yl-hexamethylenetetramine (C3.5) (500 mg, 2.54 mmol), 8-bromo-5-(methylthio)- (/1,2,4|triazolo|4,3- c|Ipyrimidine (3) (320 mg, 1.30 mmol) in OSM (2 mL) was heated at 502C in an open vessel overnight. The reaction mixture was purified by column chromatography ( silica gel, eluting

EUAs in 1095 RE - 50,965; then MeOH in 195 OSM - 3.5 95) to give the target compound as a yellow solid (230 mg, 46 95). "H NMR (500 MHz, SOSI3) b ppt 3.20 (d, 1H), 3.44 (dd, 1H), 3.48 (s, ЗН), 4.79-4.69 (t, 2H) , 5.63 (dd, 1H), 6.65 (dd, 1H), 6.79 (t, 1H), 6.97 (t, 1H), 7.79 (s, 1H), 9.10 ( p. 13). SM: MANI" -394.0.

Example 1 8-(1,3-dimethyl-1H-pyrazol-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine

Kk

R. Dyan, t m. .MN X K | what r BATTLE zi o u o u s o VI What

I M Su di Wu -i vu KT MAMO MM

M-M MM. di Example and

1,3-dimethyl-1H-pyrazole-5-ylboronic acid (43.2 mg, 0.41 mmol) was added to a solution of A1 (70 mg, 0.19 mmol) in dioxane (3 mL) and H2O (1 mL) ), MnSOSO:z (49 mg, 0.58 mmol) and Pa(arrOSi) (14.1 mg, 0.019 mmol). The mixture was heated at 95 °C and stirred for 40 min, then concentrated under reduced pressure. The crude product was purified preparative HPLC to obtain the target compound (11 mg, 15 95) in the form of a white solid." ), 3.73 (c, ЗН), 4.55 (t, 2H), 4.72 (c, 2H), 6.29 (c, 1H), 6.72 (dd, 1H), 6.95 (dd, 1H), 7.74 (s, 1H), 8.84 (s wid., 1H), 9.47 (s, 1H). CM: (MANI -380 2.

Example 2

Methyl-M-(5-Fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-methylpyridin-3-yl)-P1,2,4|griazolo4,3-c|Ipyrimidin-5-amine eE sk o M. plural

M. Mn Phi ? ho | AND! | IY s eh --. "IN. With se

BUT; br - fo in m mo

M-M and Example 2

(2-Methylpyridin-3-yl)/boronic acid ( 30.1 mg, 0.220 mmol), potassium carbonate (45.5 mg, 0.330 mmol) and Ra(RizR) (12.69 mg, 10.98 μmol). The resulting mixture was stirred in a Ma atmosphere at 1109C for 3 hours, cooled to room temperature and evaporated under vacuum. The residue was purified by flash chromatography (OSM:Meon-10:1) to give Example 2 as a white solid (20 mg, 46.0 Vol).

Also, Example 2 was obtained as follows. To a suspension of AT (25.5 g, 70 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30.6 g, 140 mmol) and ManSO3 (35.3 g, 420 mmol) in a solution of a mixture of 1,4-dioxane (300 ml) and H2HO (100 ml) was added Rasi»z(arry) (5.94 g, 612 mmol). The mixture was degassed M", heated at 110 C for 1 hour. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (EFAs:MeOH-20:1) to obtain 14 g of the desired product. 200 ml of acetone was added to the product, and the resulting suspension was heated at 50°C for 2 hours. The white solid was collected by filtration and dried under vacuum to give Example 2 (13.6 g, 52,965) "H-NMR (500 MHz, OM50O-av) bpp 2.40 (s, ЗН), 3.43 (t , 2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.96 (dd, 1H), 7.41 (dd, 1H), 7 .66 (s, 1H), 7.74 (d, 1H), 8.51 (d, 1H), 8.72 (t, 1H), 9.49 (s, 1H). SM: М-А- NO-376.9.

To the suspension of Example 2 (6.0 g, 15.94 mmol) in 100 ml of IRA, 0.5 n. solution of NSI in IRA (33.0 ml,

of 16.50 mmol) was added dropwise at room temperature. The suspension was stirred at 5020 for 12 h, then cooled to room temperature and stirred for 5 h. The resulting solid was collected by filtration and dried at 402C under vacuum for 2 days to obtain the hydrochloride salt of Example 2 in the form of a white solid (6.5 g, 98 95) "H NMR (О0М50-ав) 6 ppt 2.65 (s , ZH), 3.45 (t, 2H), 4.57 (t, 2H), 4.74 (d, 2H), 6.73 (dd, 1H), 6.97 (dd, 1H), 7 .83 (s, 1H), 7.85-7.94 (t, 1H), 8.46 (d, 1H), 8.80 (dd, 1H), 9.07 (t, 1H), 9, 58 (c, 1H). HOM5: MANI: -376.9.

Example C 8-(2,4-dimethylpyrimidin-5-yl)-N-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine -0 i--o pcs

N U u o M. ve

MM their ri : | Y t G tires are forged

PI SK ry

M-M yes in Example C

The target compound was obtained using a procedure similar to that of Example 1, by replacing 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with B1. "H NMR (500 MHz, OM5O-dv) 6 2.49 (s, ЗН), 2.65 (s, ЗН), 3.43 (t, 2Н), 4.56 (t, 2Н), 4, 73 (d, 2H), 6.73 (dd, 1H), 6.97 (dd, 1H), 7.72 (s, 1H), 8.60 (s, 1H), 8.83 (s width. , 1H), 9.50 (s, 1H). SM: (Me -392.1.

Example 4

Methyl-M-(5-Fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidin-5-amine o /to sa

KO, y y

Nn and no / Mayor of them

Mate u know u ME

Yii kyu! OM syu dit rya E -M M i TSI Hy

VO » in М-М-М

M-M /y - di vag Example 4

The target compound was obtained using a procedure similar to that of Example 1, by replacing 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with B2. "H-NMR (400 MHz, OM50O-dv) b ppt 1.43 (d, 6H), 2.45 (s, ЗН), 3.40 (t, 2H), 4.48-4.56 (t , ZH), 4.69 (d, 2H), 6.70 (dd, 1H), 6.95 (dd, 1H), 7.73 (c, 1H), 8.40 (c, 1H), 8 .50 (with width, 1H), 9.45 (with, 1H). I EM: IM'-NI: -408.2.

Example 5

Methyl-M-(5-Fluoro-2,3-dihydrobenzofuran-4-yl))-8-(b-methoxy-4-methylpyridin-3-yl)-

P1,2,4Hygriazoles|4,3-c|Ipyrimidin-5-amine o; lo Ya A

HK sb - i so : ; ; Man, -y

M.N -, A.Ya or KM, R! and | . And and What And in, And "because in WE

MAM

As in Example 5

The target compound was obtained using a procedure similar to that of Example 1, by replacing 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with B3. "H NMR (500 MHz, OM5O-dv) 6 2.18 (s, 3H), 3.45 (t, 2H), 3.88 (s, 3H), 4.56 (t, 2H), 4, 71 (d, 2H), 6.73 (dd, 1H), 6.81 (s, 1H), 15. 6.96 (dd, 1H), 7.59 (s, 1H), 8.07 (s , 1H), 8.68 (with width, 1H), 9.46 (with, 1H). I CM: MANI: -407 1.

Example 6 8-(6b-cyclopropyl-2-methylpyridin-3-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)-methyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidin-5-amine and a chi ze cat i c) M K Ah r

KA U ov unchaya

XX year

M E - r Y vb ny she y ve M-M m-Ki o; with M

A1 and Example b

The target compound was obtained using a procedure similar to that of Example 1, by replacing 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with B4. "H NMR (400 MHz, OM5O-dv) b ppt 0.90-0.97 (t, AN), 2.09-2.13 (t, 1H), 2.41 (s, ЗН), 3, 40 (t, 2H), 4.55 (t, 2H), 4.71 (s, 2H), 6.71 (dd, 1H), 6.96 (dd, 1H), 7.18 (d, 1H ), 7.56-7.60 (t, 2H), 8.68 (with width, 1H), 9.46 (with, 1H). And CM5:

IM-ANI-417 2.

Example 7 (3-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazolo|4,3-c|pyrimidin-8-yl) upyridin-2-yl)umethanol log /ta

Yes! t TI it yi | -79 ry tn KI, "MONO and AIV. и, BO Y KO Y vu a Ok pany PO V m-m otv5 M 7 MO tvo no di vo 74 Example t? 8-(2-((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-M-(5-fluoro-2,3-dihydro-benzofuran-4-ylylmethyl)-(1,2,4) griazolo|4,3-c|Ipyrimidin-5-amine (7,1): The title compound was prepared by a procedure similar to that of Example 1 by substituting 1,3-dimethyl-1H-pyrazol-5-ylboronic acid for B5. AND! SM: (MANI -507.1.

Example 7: TVAE (0.6 ml, 0.6 mmol) was added to a mixture of 7.1 (30 mg, 0.08 mmol) in TNE (3 ml) and stirred for 4 h. The mixture was concentrated and purified by preparative HPLC to give the target compound (20 mg, 87 95) as a white solid. "H-NMR (500 MHz, OM50-dv) b ppt 3.44 (t, 2H), 4.51 (d, 2H), 4.57 (t, 2H), 4.73 (d, 2H), 5.11 (t, 1H), 6.72 10. (dd, 1H), 6.74 (dd, 1H), 7.44 (dd, 1H), 7.76 (s, 1H), 7.89 (dd, 1H), 8.61 (dd, 1H), 8.74 (with width, 1H), 9.48 (s, 1H). HOM5: MANI -393. 1.

Example 8 8-(2-cyclopropyl-4-methylpyrimidin-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)-methyl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidin-5-amine dk c) ak I MA

Zh. Y

I TO o G data in vn what. M E in HC shY tso. what 1 ; Mm

And others -M

And "U sum di va Example 8

The target compound was obtained using a procedure similar to that of Example 1, by replacing 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with B8. "H-NMR (400 MHz, OM5O-dv) b ppt 1.04-1.08 (t, 4H), 2.21-2.24 (t, 1H), 2.46 (s, ЗН), 3 .43 (t, 2H), 4.56 (t, 2H), 4.72 (d, 2H), 6.72 (dd, 1H), 6.96 (dd, 1H), 7.71 (s, 1H), 8.53 (s, 1H), 8.80 (s width, 1H), 9.48 (s, 1H). And CM5:

IMANI-418,1.

Example 9

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-isopropoxy-4-methyl-pyrimidin-5-yl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine lo

WITH

SYA Ge aa gu shi: tok that -koo viya! - ! | and

Ve y mo olmeya MM

M-M r A di I Example 9

The target compound was obtained using a procedure similar to that of Example 1, by replacing 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with B10. "H-NMR (400 MHz, OM50O-dv) b ppt 1.45 (d, 6H), 2.44 (s, ЗН), 3.46 (t, 2H), 4.57 (t, 2H), 4.72 (s, 2H), 5.28 (t, 1H), 6.72 (dd, 1H), 6.97 (dd, 1H), 7.68 (s, 1H), 8.47 (s , 1H), 8.76 (with width, 1H), 9.48 (with, 1H). SM: IM.--NI-436,1.

Example 10

Zo 3-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)amino)-(1,2,4A)griazolo|4,3-c|pyrimidin-8-yl)upyridin 1 -ke oxide; I 3 and from m. Mn is m. Mn r yo poko E Ж Щ і mai ay kosh V. r payati M E o--0 Har chi yy

Ak Ya Ya Senya et tki we her m-m o di 501 Example 4160

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(pyridin-3-yl)-(1,2,4|griazolo4,3- cIpyrimidin-5-amine) (10.1) : The title compound was prepared by a procedure similar to that of Example 1 by substituting 1,3-dimethyl-1H-pyrazole-5-ylboronic acid with 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine. Example 10: To a mixture of 10.1 (110 mg, 0.4 mmol) in NaCl (5 mL) was added tsRBA (163 mg, 0.6 mmol). The reaction mixture was stirred for 16 h at room temperature. temperature. The mixture was concentrated and purified by preparative HPLC to give the target compound (7 mg, 6 95) as a white solid. "H NMR (500

MHz, ОМ50О-ав) b ррт 3.40 (s, 2Н), 4.55 (t, 2Н), 4.74 (s, 2Н), 6.72 (dd, 1Н), 6.95 (dd, 1H), 7.51 (dd, 1H), 8.12 (d, 1H), 8.19 (d, 1H), 8.42 (d, 1H), 8.98 (c, 1H), 9, 17 (c, 1H), 9.52 (c, 1). ISM5:

IMANIG-379,2.

Example 207

Methyl-M-(5-Fluorobenzofuran-4-yl))-8-(2-methylpyridin-3-yl)-I1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine de Dt in de m. M ХК 1 o-K More m EK i o what: и Go hi for You | i-th bottom I M ke x t o 65235 and how

Вги и у; in th U Ki Kh

M-m M ek M-m

M - t "

To a solution of 8-bromo-M-(5-fluorobenzofuran-4-yl)methyl)-(1,2,4|griazolo|4,3-s|Ipyrimidin-5-amine (C1) (50 mg, 0.14 mmol) in dioxane (2 ml) was added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (45 mg, 0.21 mmol), Ra (arrOsi" (23 mg, 0.028 mmol), Mansose (35 mg, 0.42 mmol) and water (1 mL). The reaction mixture was purified by Me" 3 times, then stirred at 9026 for 1 h. The mixture was filtered, the solid was washed OM5BO (2 ml). The filtrate was concentrated and purified by preparative HPLC (MNaANSO") to give the target compound (13 mg, 48 95) as a white solid. "H-NMR (400 MHz, OM50-α6) b pprt 2, 40 (c,

ЗН), 5.01 (s, 2H), 7.21-7.25 (t, 2H), 7.41 (dd, 1H), 7.62 (dd, 1H), 7.66 (s, 1H ), 7.75 (d, 1H), 8.08 (d, 1H), 8.50 (t, 1H), 8.86 (c, 1H), 9.46 (c, 1). SM: (MANI -375.1.

Example 233

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-methyl-1H-imidazol-1-yl)-

P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine

M. is about S X and M. and m scha ХК in -- Yu| howl

Zh m - shi UM --

Wo y; Vg them I:

MM MM

Adi schy Sa B t bos G Y M. M. AD -M. M. rad t M i ge o v V,

M in ut Mch-mM in M-M / c4i2 Appl. 233 tert-butyl-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl(8-(4-methyl-1H-imidazol-1-yl )-

From P1,2,4Hygriazolo|4,3-c|Ipyrimidine-5-ylcarbamate (C4.2): a suspension of Raz(aba)z (18 mg, 0.02 mmol) and

Me--I-Vykh Roz (19.2 mg, 0.04 mmol) in 1.0 ml of anhydrous dioxane was heated at 1002С for 10 minutes in an atmosphere of M". The resulting mixture was transferred to an active suspension of C4.1 (90 mg, 0.2 mmol), 4-methyl-1H-imidazole (72 mg, 0.88 mmol) and KzPO4 (110 mg, 0.52 mmol) in 2.0 ml of anhydrous dioxane. The reaction mixture was stirred at 1209C overnight, then cooled to room temperature and filtered, the solid residue was washed several times with EtOAc. The filtrate and EIOAc washes were combined and concentrated under reduced pressure to give crude product C4.2, which was used in the next step without purification.

SM: IM-ANI -466.2.

Methyl-M-(5-Fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-methyl-1H-imidazol-1-yl)-

P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine (233): a solution of C4.2 (93 mg, 0.2 mmol) in 6 ml of 1,1,1,3,3,3-hexafluoropropane -2-ol was heated in a Vioiade microwave reactor at 1002C for 1 hour. The solvent was removed under vacuum to give a yellow oil and purified by prep

HPLC to give the title compound as a white solid (19 95 yield 8 mg). "H NMR (500 MHz, OM5O) 5 ppt 2.19 (s, 3H), 41 (t, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 6.71 (dd , 1H), 6.93-6.98 (t, 1H), 7.53 (s, 1H), 7.99 (s, 1H), 8.25 (d, 1H), 8.78 (s, 1H), 9.52 (s, 1H). GSM5:

IMANI-366,1.

The following compounds identified in Table 2 were prepared using the general procedures as well as the procedures of the examples described above with suitable starting materials and reagents.

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 Fr

Max

M M M b ppt 2.18 (s, 6H), 3.25 (t, 2H), 3.43 (s, 2H), 4.56 (t, 2H), 11 I 4.72 (s, 2H ), 6.70 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.48 (d,

In 2H), 8.01 (s, 1H), 8.05 (d, 2H), 8.80 (s, 1H), 9.51 (s, 1H).

CM: MANI -401.2

H

M

/ and;

N

Mach is 1

M m-K H-NMR (400 MHz, SOzOB) b ppt 3.12-3.13 (t, 1H), 3.17 12 Be |! (c, ЗН), 3.47-3.48 (t, 1H), 4.58 (t, 2H), 4.82 (c, 2H), 6.68 shui (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H), 8.05 (d, 2H), 8.12 (s, 1H), 8.27 (d, 2H), 9.42 (s, 1H) . GSM5: MANI -421.8 ih

Хх оо о) "H-NMR (400 MHz, COzOb) b ppt 3.13-3.14 (t, 1H), 3.47-

M M 3.48 (t, 1H), 4.58 (t, 2H), 4.79 (s, 2H), 6.68 (d, 1H), 6.92 13 vii (d, 1H), 7 .09 (t, 1H), 7.49 (d, 1H), 7.47 (d, 1H), 7.50-7.51

M (t, 2H), 7.89-7.91 (t, ЗН), 9.42 (c, 1H). And SM5: in IMANI-343.9

М-М 5О0

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 (o) ke that "H-NMR (400 MHz, COzOV) b rt 1.57-1.58 (t, ZN), 1.90-

We 1.92 (t, 4H), 2.73-2.74 (t, 2H), 2.94-2.95 (t, 2H), 3.26- 14 - M 3.27 (t, 2H ), 3.74-3.75 (t, 1H), 4.56 (t, 2H), 4.78 (s, 2H), 6.66 (d, 1H), 6.90 (d, 1H) , 7.06 (t, 1H), 7.51 (d, 2H), 7.93-

F 7.95 (t, ZN), 9.42 (s, 1H). Um: MANI -440.9

M e); I am in

Mk - "H-NMR (400 MHz, COzOS) 5 ppt 2.74 (s, 6H), 2.42 (t, 15 - UM 2H), 4.82 (s, 2H), 5.49 (s, 2H), 6.68 (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H), 7.89 (d, 2H), 8.10 (s, 1H), 8, 24 (d, 2H), 9.44 (s, 1). hom: IMANI -450.8 o, -mo y (F)

H b ppt 3.25 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 16 M. and M 6.89 (d, 1H), 7.08 (t, 1H), 7.50 (dd, 1H), 8.14 (s, 1H), 8.51 m (t, 1H), 8.55 (t, 1H), 8 .94 (c, 1H), 9.28 (d, 1H), 9.53 (c, 1H). d / and 7; And SsM85: (MANI -345.1 /

M-- )

H "H-NMR (400 MHz, COzOB) 5 ppt 3.48-3.50 (t, 2H), 4.58 17 M. M (t, 2H), 4.83 (s, 2H), 6, 68 (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H), 8.14-8.15 (t, 2H), 8.25 (s, 1H), 8.59 -8.61 (t, 2H), 9.44 (s, d 7.1). cm: (MANI -344.9 x

M | M-M

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (e);

M in

Me - "H-NMR (400 MHz, SOzOB) b ppt 2.48 (s, ЗН), 2.63-2.64 -M (t, 4H), 3.48-3.49 (t, 2H) , 3.64-3.65 (t, 4H), 4.57 (t, 2H), 18 4.81 (s, 2H), 6.68 (d, 1H), 6.91 (d, 1H) , 7.09 (t, 1H), 7.24 (d, 4 M 1H), 7.63 (s, 1H), 8.15-8.17 (t, 2H), 9.43 (s, 1H ).And CM5:

Mo IMANI-442.9

Also

M

Ge) shk SO

M. M- "H-NMR (400 MHz, SOzOB) b ppt 3.01 (s, ЗН), 3.47-3.48 19 M (t, 2Н), 4.57 (t, 2Н), 4 .79 (s, 2H), 6.68 (d, 1H), 6.91 (d, 1H),

Che: 7.09 (t, 1H), 7.47 (d, 2H), 7.91-7.92 (t, ЗН), 9.41 (s, 1H). o SM: (MANI -436.8 ov. / N o) m v

M

M i b ppt 2.22 (s, 3H), 2.41 (s, 4H), 3.23 (t, 2H), 3.54 (s, 4H), which is 4.54 (t, 2H) , 4.69 (s, 2H), 6.68 (d, 1H), 6.87 (d, 1H), 6.93 (d, m 1H), 7.05 (d, 1H), 7.94 (c, 1H), 8.24 (d, 1H), 8.74 (c, 1H),

M 8.82 (s, 1H), 9.47 (s, 13). I SEM5: MANI: -442.9 and r

Table 2

Pr. "H NMR (400 MHz, OM5O-v)

Mo Structure or otherwise shown/data | CM5 (o)

A SO and CHO, "H-NMR (400 MHz, SOzOB) b ppt 3.97 (s, ZH), 4.55-4.60 24 M xx sht (t, 2H), 4.79 (s, 2H ), 5.49 (s, 2H), 6.67 (d, 1H), 6.90-6.94 -- (t, 2H), 7.09 (t, 1H), 7.90 (s, 1H), 8.21-8.23 (t, 1H), 8.69 y, (d, 1H), 9.42 (s, 1). GSM5: MANI: -374.9 m pc -zO

IF) "H-NMR (400 MHz, СозЗОБ) b ррт 1.21-1.28 (t, ЗН), 2.40 mo Kk (с, 6Н), 2.85-2.91 (t, 1Н) , 3.41-3.42 (t, 1H), 3.47-3.54 (t, 22 | g 1H)U, 4.08 (s, 2H), 4.79 (s, 2H), 6 .63 (d, 1H), 6.89 (d, 1H),

M 7.09 (t, 1H), 7.44 (d, 2H), 7.89-7.91 (t, ЗН), 9.41 (s, 1H). schu; I. SM: (Men -414.9

M M-M

Ge; also mo M M m "H-NMR (400 MHz, СозОБ) b ррт 2.43 (s, 6Н), 3.49-3.41 23 B o (t, 2Н), 3.72-3.73 ( t, 2H), 4.60 (t, 2H), 4.85 (s, 2H), 6.67 -- U (dd, 1H), 6.88 (t, 1H), 7.49 (d, 2H), 7.95-7.99 (t, ZN), 9.46 (s, 183. CM: MANI -419.1

H

M

/ o m-x M E same ЧО b ррт 2.06 (s, ЗН), 2.15 (s, ЗН), 3.25 (t, 2Н), 3.72 (s, ЗН), ha Ma Ш 4.55 (t, 2H), 4.68 (d, 2H), 6.69 (d, 1H), 6.89 (d, 1H), 7.08 (t,

M 1NU, 7.44 (s, 1H), 8.67 (s, 1H), 9.45 (s, 13). I. CM5:

She IMANE-376.2 "sh)

M

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (0)

N

Mach E | b ppt 3.23 (t, 2H), 3.91 (s, ЗН), 4.54 (t, 2H), 4.67 (d, 2H),

M

M. pieces 6.68 (d, 1H), 6.86 (d, 1H), 7.06 (t, 1H), 8.00 (s, 1H), 8.11 (s,

M 1H), 8.43 (s, 1H), 8.66 (t, 1H), 9.47 (s, 13). And CM5:

She IMANI-348,1 what

M,

M

/ (0)

Mach M. S

M M "H-NMR (400 MHz, COzOb) b ppt 3.22 (s, ЗН), 3.28-3.29 26 B i (t, 2Н), 4.59 (t, 2Н), 4, 83 (c, 2H), 6.70 (d, 1H), 6.94 (d, 1H),

K - M 7.10 (t, 1H), 7.86-7.92 (t, 2H), 7.99 (s, 1H), 8.13-8.16 (t, 1H), 9.45 (c, 1). SM: |MANI:-440.1

J

Zh oo (o;

N

Mach in "H-NMR (400 MHz, SOzOB) b ppt 3.24 (s, ЗН), 3.45-3.46 27 M: M (t, 2H), 4.59 (t, 2H), 4 .83 (c, 2H), 6.69 (d, 1H), 6.94 (d, 1H),

W 7.11 (t, 1H), 7.77 (t, 1H), 7.98 (d, 1H), 8.08 (c, 1H), 8.40 (d, o-i 1H), 8 .59 (c, 1H), 9.47 (c, 1). SM: MANI -422.1 o (o);

N

Mach M. S

M m-K "H-NMR (400 MHz, COzOb) b ppt 3.27-3.29 (t, 5H), 4.59 28 B x (t, 2H), 4.84 (s, 2H), 6.69 (d, 1H), 6.94 (d, 1H), 7.11 (t, 1H), - U 8.19 (d, 1H), 8.23 (s, 1H), 8.76 (d, 1H), 9.47 (s, 1H), 9.42 (s, and 1n). Sm: (MANI -423.1 m

I sht vh oo

Table 2

Pr. "H NMR (400 MHz, OM5O-v)

Mo Structure or otherwise shown/data | CM5 (F;

Me in

We found 1.47 (t, 2H), 1.75 (d, 2H), 2.41 (t, 2H), 2.96 (d, 2H), x

M 3.25 (t, 2H), 3.43 (t, 2H), 4.55 (t, 2H), 4.74 (s, 2H), 6.70 (d, 29 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.89 (d, 2H), 8.25 (s, 1H), 8.45 (d, 2H), 9.05 (s, 1H) , 9.55 (c, 1H). SM: o (Man -491.0 0

WE

(at;

M N ; A mech M b rrt 2.43 (s, ZN), 3.23 (t, 2H), 3.83 (s, ZN), 4.54 (t, 2H), zo Mach - 4.68 (s, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t, 1H), 7.70 (s,

M 1H), 8.28 (s, 1H), 8.63 (s, 1H), 9.47 (s, 13). I. CM5:

She IMANI-362,2 what

M,

M

/ about;

Me ve "H-NMR (400 MHz, СозОБ) b ррт 3.28-3.29 (t, 2Н), 4.59 31 / MM M (t, 2Н), 4.81 (с, 2Н), 6 .70 (d, 1H), 6.94 (d, 1H), t (t, 1H),

Mu i 7.25 (t, 1H), 7.29 (d, 1H), 7.43-7.49 (t, 1H), 7.76-7.78 (t,

Kk - 1H)U, 7.83 (s, 1H), 9.46 (s, 1H). ISM5: (MANI: -362.1 o)

M- o "H-NMR (400 MHz, COzOB) b ppt 3.40 (s, 2H), 4.59 (t, 32 M. x- 2H), 4.81 (s, 2H), 6.69 (d, 1H), 6.94 (d, 1H), 7.11 (t, 1H), si X 7.A3-7,A46 (t, 2H), 7.54-7.59 (t, 2H ), 7.70 (s, 1H), 9.42 (s, - 18). SM: MNE -378.2

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5

F) M. M. Io

М. ), 6.88 (d, 1H), 7.07 (t, 1H), 7.46 (t, 1H), 7.97

Che: (dd, 1H), 8.15 (t, 2H), 8.92 (s, 1H), 9.49 (s, 1H), 9.52 (s, b 18). SMm5: (MANI -454.9 sho TSI osv / N

Gee)

Mel in

M.:yu - b ppt 3.21 (t, 2H), 3.75 (s, 2H), 4.19 (t, 2H), 4.52 (t, 2H),

ACCORDING TO M 4.66 (s, 2H), 4.93 (s, 1H), 6.68 (d, 1H), 6.86 (d, 1H), 7.05 (t,

SHE: 1H), 8.00 (s, 1H), 8.12 (s, 1H), 8.45 (s, 1H), 8.66 (s, 1H),

M M 9.45 (p, 1). CM: MANI -378.2

In, but (about)

Mel v

I have M b rrt 2.19 (s, 6H), 2.47 (t, 2H), 2.74 (t, 2H), 3.24 (t, 2H), - F 4.55 (t, 2H) , 4.71 (d, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.41 (d, 2H), 7.98 ( d, 2H), 8.03 (s, 1H), 8.80 (s, 1H), 9.51 (s, 1H). SM: (MANI -415.0 t

M

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 0)

Mel in

M

Mu i b rprt 2.24 (s, ZN), 2.41 (s, ZN), 2.50 (t, 4H), 3.12 (t, 4H), 36 - U 3.24 (t, 2H ), 4.55 (t, 2H), 4.71 (s, 2H), 6.69 (d, 1H), 6.87 (d,

M 1H), 7.07 (t, 1H), 7.99 (s, 1H), 8.20 (d, 1H), 8.77 (d, 1H),

X 8.82 (c, 1H), 9.50 (c, 1). I SEM5: MANI: -457.0 sy ra (9)

Mel in

M. kt E b rrt 3.27 (s, ZN), 3.43 (d, 2H), 4.56 (t, 2H), 4.76 (s, 2H), 37 M 6.72 (dd, 1H), 6.97 (t, 1H), 8.00 (d, 2H), 8.27 (s, 1H), 8.46

She: (d, 2H), 9.55 (s, 1H). And CM5: IMAANI-440,1

M oo u

M fa "H-NMR (500 MHz, OM50O-av) b rprt 3.25 (t, 2H), 3.74 (t, 38 M 2H), 4.04 (t, 2H), 4.55 (t , 2H), 4.71 (c, 2H), 4.89 (t, 1H), sc, 6.69 (t, 1H), 6.88 (t, 1H), 7.06 (t, ЗН) , 7.94 (s, 1H), 8.04 (t, 1H), 8.71 (t, 1H), 9.50 (s, 1H). SM: MANI -404 4 no-/77o

F)

Mel in

ММЕ b ррт 3.26 (s, ЗН), 3.43 (s, 2H), 4.55 (t, 2H), 4.75 (s, 2H), 39 - M 6.71 (t, 1H), 6.96 (t, 1H), 8.00 (d, 2H), 8.27 (s, 1H), 8.46

E (d, 2H), 9.52 (s, 13). cM5: MANI -473.2 o-9 x8-M / N

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 o) mech c

Mach dk b rrt 2.79-2.82 (t, 2H), 3.20-3.24 (t, 2H), 3.46-3.40 (t, -- M 2H), 4.51- 4.55 (t, 2H), 4.67 (s, 2H), 6.64 (d, 1H), 6.90 (d, 1H), 7.02 (t, 1H), 7.78 (d , 2H), 8.15 (c, 1H), 8.44 (d, 2H), o 9.23 (c, 1). SM: MANI -467.1 st

IF)

M in

Mach M "H-NMR (400 MHz, СОзОб) b ррт 2.82-2.93 (t, AN), 3.49- d Ж 3.51 (t, 2Н), 3.76-3.77 ( t, 2H), 4.59 (t, 2H), 4.81 (s, 2H), 6.69 (d, 1H), 6.93 (d, 1H), 7.09 (t, 1H), 7.55 (d, 2H), 8.02 (s, 1H), 8.08 (d, 2H), 9.45 (s, 1H). SM: MANI: -456.2 nm ), , (d , ), , (c, ) I I 56, ich (c) (F); meh E

Ma M "H-NMR (400 MHz, SOzOB) bpp 3.09 (s, ЗН), 3.15 (s, to M ЗН), 4.59 (t, 2Н), 4.82 (s, 2Н ), 6.69 (d, 1H), 6.93 (d, 1H), cx 7.10 (t, 1H), 7.57 (d, 2H), 8.03 (s, 1H), 8, 07 (d, 2H), 9.45 (s, 18). EmM5: (MANI -415.2

H

M

/ (is); (at)

Mach CO "H-NMR (400 MHz, СОзОБ) b ррт 3.09 (s, ZN), 3.15 (s, 43 M s M ZN), 4.59 (t, 2Нn), 4.82 (s , 2Hn), 6.69 (d, 1H), 6.93 (d, 1Hn), and M 7.10 (t, 1H), 7.57 (d, 2H), 8.03 (s, 1H) , 8.07 (d, 2H), 9.45 (s,

Moscow 1n). som: (M.N -415.2

IF)

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 Fr

H "H-NMR (400 MHz, COzOB) bpp 3.41 (t, 2H), 4.60 (t, 44 Mo and M 2H), 4.85 (s, 2H), 6.65-6, 68 (t, 1H), 6.88 (t, 1H), 7.56-7.59 in (t, 1H), 8.09 (s, 1H), 8.44-8.47 (t, 1H ), 8.55 (d, 1H), 9.16 d / ' and E (s, 1H), 9.47 (s, 18). I CM: MANI -363.1 /

M--

ZM M o

H "H-NMR (400 MHz, COzOB) b ppt 3.41 (t, 2H), 4.60 (t, 45 My M 2H), 4.87 (s, 2H), 6.66-6.69 (t, 1H), 6.88 (t, 1H), 8.15-8.17 (t, 2H), 8.40 (c, 1H), 8.60-8.62 (t, 2H), 9.48 (s, 1H). d ME ISsM8:1 cm: Man -363.1

Her and

M shcha M-M ge) ke; eat "H-NMR (400 MHz, MeOH-a4) 5 ppt 1.48 (d, ZN), 1.82-1.85

We are E | (t, 4H), 2.46-2.50 (t, 2H), 2.68-2.70 (t, 2H), 3.47-3.42 (t, 46 - ЗН), 4.60 (t, 2H), 4.83 (s, 2H), 6.65-6.68 (t, 1H), 6.88 (t, 1H), 7.49 (d, 2H), 7.90 (d, 2H), 7.96 (c, 1H), 9.45 (c, 1H).

FI SM: |MaNG-459,2

M is)

H-NMR (400 MHz, SOZOB) 5 ppt 3.46-3.43 (t, 2H), 4.60 47 M muz (t, 2H), 4.86 (s, 2H), 6 ,66-6.69 (t, 1H), 6.89 (t, 1H), 7.40- in: 7.44 (t, 1H), 7.96 (s, 1H), 8.60-8 .63 (t, 1H), 8.99 (d, 1H), and -- U 9.46 (s, 1H). I S-I. SM: (MANI -381 1

M

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (Fo;

M. M "H-NMR (400 MHz, COzOb) b ppt, 3.15-3.28 (t, 2H), 4.54 48 im (t, 2H), 4.69 (d, 2H), 6 .08 (d, 2H), 6.54 (d, 1H), 6.69 (d, 1H), w- 6.87 (d, 1H), 7.07 (t, 1H), 7.86 ( s, 1H), 8.05 (k, 1H), 8.66 (d, cha i 2H), 9.48 (s, 1). SM: IMANI-360.2 she

NOM

IF) m c

M. M "H-NMR (400 MHz, SOzOB) b ppt 2.26 (s, ZN), 2.81 (s, 49 M ZN), 3.03 (s, ZN), 3.25 (t, 2H), 4.53 (t, 2H), 4.72 (s, 2H), s: 6.69 (d, 1H), 6.88 (d, 1H), 7.06 (t, 1H), 7.23 (d, 1H), 7.97 (t, ZN), 8.86 (s, 1H), 9.51 (s, 1H). SM: (MANI -429.5

H

M

/ (c) o

M- o "H-NMR (400 MHz, COzOb) bpp 3.24-3.40 (t, 2H), 4.56

BO cha M (t, 2H), 4.72 (d, 1H), 6.71 (d, 1H), 6.91 (d, 1H), 7.08 (d, 1H),

SI them 7.72 (s, 1H), 7.76 (s, 1H), 8.59 (d, 1H), 8.72 (s, 1H), 9.50 (s, 1 each). Sm5: MANI -378.9 ac

M

(F)

M So b rprt 3.25 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.71 (d, 1H), 51 | in 6.90 (d, 1H), 7.06 (t, 1H), 8.28 (s, 1H), 9.15 (s, 1H), 9.54 (s, d M ZN). SM: (MANI -346.5

Gu

M M

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (F)

Mach CO b ppt 2.49 (s, 4H), 3.24 (t, 2H), 4.54 (t, 2H), 4.71 (s, 2H),

Because M. M 6.69 (d, 1H), 6.86 (d, 1H), 7.06 (t, 1H), 7.44 (d, 1H), 8.07 (s,

M 1H), 8.48 (d, 1H), 9.13 (c, 1H), 9.50 (c, 13). CM5: according to IMANI-359.2 m pcs (o) I ve

I have M b ppt 2.28 (s, 6H), 2.75 (t, 2H), 2.96 (t, 2H), 3.26 (t,

BZ - F 2H), 4.57 (t, 2H), 4.72 (t, 2H), 6.70 (d, 1H), 6.89 (d, 1H), y, 7.09 (t, 1H), 7.41 (d, 1H), 8.09 (s, 1H), 8.95 (t, 1H), 9.40 cm (t, 1H), 9.52 (s, 1). SM5: (MANI -416 2 t

M u

M

In M b ppt 3.19-3.25 (t, 2H), 3.97 (s, ЗН), 4.52-4.56 (t, 2H), 4.71

BA Mach same (s, 2H), 6.68-6.70 (d, 1H), 6.86-6.88 (d, 1H), 7.05-7.08 (t, - M 1H), 8.12 (s, 1H), 9.29 (s, 2H), 9.51 (s, 1H). CM5: ; IMANI-376.4

Zm -o (F); meh o

M. ME |" H-NMR (400 MHz, COzOr) bpp 3.09 (s, ZN), 3.15 (s,

BB M ZN), 3.40 (t, 2H), 4.60 (t, 2H), 4.83 (s, 2H), 6.65-6.69 (t,

SHE: 1H), 6.87 (t, 1H), 7.57 (d, 2H), 8.06-8.08 (t, ЗН), 9.46 (s, 1). Sm5: MANI -433.2 x

M

/ (is)

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 (9)

M

H-NMR (400 MHz, SOzOB) bpp 3.41 (s, ZN), 3.44 (t,

Bb Be i 2H), 4.61 (t, 2H), 4.87 (s, 2H), 6.66-6.69 (t, 1H), 6.88 (t, -/M 1H), 8 .19 (d, 1H), 8.26 (c, 1H), 8.77 (d, 1H), 9.49 (c, 1H), and 9.42 (c, 1H). SM: MANI -441.1

M p o o (F)

M-so "H-NMR (400 MHz, COzOB) b ppt 2.61 (s, ЗН), 3.41 (t, 57 M. M-K E 2H), 4.60 (t, 2H), 4 .84 (s, 2H), 6.65-6.68 (t, 1H), 6.88 (t,

M 1H), 7.44 (d, 1H), 8.04 (s, 1H), 8.41 (d, 1H), 9.00 (s, 1H), -SHUO 9.46 (s, 1H) . G CM: MANI -37 7.2.

M - Shn xg (F)

M in

Mach M b rprt 3.25 (t, 2H), 4.55 (t, 2H), 4.72 (d, 2H), 6.71 (k, 2H), 58 -- 6.87 (d, 1H ), 7.08 (t, 1H), 7.65 (c, 2H), 8.44 (d, 1H), 8.79 (c, n 1H), 9.47 (c, 13). GSEM5 MANI: -378.5

M

Customs

HM Fr

N

Ma in | b ppt 2.20 (s, ЗН), 2.48 (s, ЗН), 3.25 (t, 2Н), 4.56 (t, 2Н),

M

59 I have pcs 4.70 (s, 2H), 6.71 (d, 1H), 6.90 (d, 1H), 7.09 (d, 1H), 7.65 (s,

M 1H), 8.87 (s, 1H), 9.48 (s, 1). And SM5 MANI: -363.2 pcs

M

Ge;

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (F)

M ke Ye b rprt 2.66 (s, ZN), 3.23 (t, 2H), 4.54 (t, 2H), 4.72 (s, 2H),

M: t 6.69 (d, 1H), 6.87 (d, 1H), 7.06 (t, 1H), 8.20 (s, 1H), 9.01 (s, -- M 1H) , 9.49 (c, 2H), 9.51 (c, 1). And SM: (MANI -360.0 m already (F)

N cha M b rrt 3.08 (s, 6H), 3.25 (t, 2H), 4.56 (t, 2H), 4.70 (s, 2H), v1 is 6.70 (d, 1H ), 6.75 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.91 (s, to 1H), 8.23 (d, 1H), 8, 80 (d, 2H), 9.49 (s, 1). And CM5:

M. H. IMANII-388.2 pcs

M

Hm

(at);

M

M- C n- b rrt 3.24 (t, 2H), 4.55 (t, 2H), 4.75 (s, 2H), 6.70 (d, 1H), in x HM 6.88 ( d, 1H), 7.07 (t, 1H), 8.13 (d, 1H), 8.49 (s, 1H), 8.86 (k, - M 1H), 9.08 (d, 1H ), 9.54 (c, 1H), 9.55 (d, 1H). And CM5:

IMANI-370.1 m pc

M

(at)

And more

М M b ррт 1.45 (t, ЗН), 3.23 (t, 2Н), 4.45 (k, 2Н), 4.55 (t, 2Н), 63 U X 4.71 (s, 2Н ), 6.69 (d, 1H), 6.89 (k, 2H), 7.07 (t, 1H), 8.01 (s, - M 1H), 8.49 (k, 1H), 8 .56 (d, 2H), 9.50 (c, 1H). And CM5:

MU and IMANII-389.0 pcs

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 (0)

N

Mach E | b ppt 2.46 (s, ЗН), 3.27 (t, 2Н), 3.81 (s, ЗН), 4.56 (t, 2Н),

M and M. units 4.69 (d, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.58 (s,

M 1H)U, 7.76 (s, 1H), 8.65 (t, 1H), 9.46 (s, 13). And CM5:

SHE: IMANI-362.0 "sh)

M

/ (about)

M Co b rrp 0.96-1.00 (t, 4H), 2.15 (t, 1H), 3.24 (t, 2H), 4.56 (t, 65 | in 2H), 4.72 (c, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H),

In B 7.49 (d, 1H), 8.06 (c, 1H), 8.46 (k, 1H), 8.87 (c, 1H), 9.07 (c, y and 1H), 9 ,51 (p. 13). SM: MANI -385.0

M M-M 6)

M ve b rrt 2.09 (s, ЗН), 2.16 (s, ЗН), 3.27 (t, 5Н), 3.69 (t, 2Н),

Mk kt 4.18 (t, 2H), 4.58 (t, 2H), 4.69 (d, 2H), 6.71 (d, 1H), 6.91 (d,

M 1H), 7.09 (t, 1H), 7.45 (s, 1H), 8.66 (t, 1H), 9.45 (s, 1H). x še I cm: IMaNI-420.7 o m.

M

(at)

M

MU, about ;

Max pc b rpt 2.08 (s, ZN), 2.18 (s, ZN), 3.27 (Kk, 2H), 3.74 (k, 2H), 67 M 4.07 (t, 2H) , 4.57 (t, 2H), 4.69 (s, 2H), 4.91 (t, 1H), 6.71 (d,

SHE: 1H), 6.91 (d, 1H), 7.09 (t, 1H), 7.44 (s, 1H), 9.15 (s, 1H),

M | 9.45 (p. 13). G CM5: (MANI -406.6

In, but

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 (9) mech vo mi 5 ppt 3.25 (t, 2H), 3.57 (d, 4H), 3.68 (s, 4H), 4.55 (t, 2H), -l 4.74 (c, 2H), 6.71 (d, 1H), 6.87 (d, 1H), 7.08 (t, 1H), 7.74 (d, y, 1H), 8.24 (c, 1H), 8.70 (k, 1H), 9.43 (d, 1H), 9.53 (c, 1H).

A m I CM5 (MANI -458.1

Ge) by,

KM

(F)

IF)

M More IN NMR (500 MHz, OM5O-av) 5 ppt 3.24 (t, 2H), 3.50 (s, i: AN), 3.73 (s, 4H), 4.55 (t, 2 H), 4.70 (s, 2H), 6.70 (d, 1H), c M 6.88 (d, 1H), 6.95 (d, 1H), 7.07 (dd, 1H), 7.96 (s, 1H), 8.28 i t, 1H), 8.76 (s, 1H), 8.86 (s, 1H), 9.50 (s, IN). SM:

And m-th (tn) (c, 1H) (c, 1H) (c, 1H)

I; (Mani-430.4 o. o.) m-x KM S

M. Zh 5 ppt 2.68 (s, ZN), 3.25 (t, 2H), 3.42 (s, ZN), 4.55 (t, 2H), 70 v i 4.74 (s, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.06 (d, 1H), 8.43 (s, -/M 1H), 8.71 (d, 1H) , 9.02 (c, 1H), 9.27 (d, 1H), 9.55 (c, 1H). and I CM: MANI -437.6 moh same w-

ХХ оо о

The IR NMR (500 MHz, OM5O-ov) b rrt 2.20 (s, ZN), 2.47 (s, 71 cha M-E ZN), 3.43 (d, 2H), 4.56 ( t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H),

M, 6.97 (t, 1H), 7.67 (s, 1H), 8.73 (s, 1H), 9.46 (s, 1H). And SM5: what (MANI -381.1

M

(at)

Table 2

Pr. "H NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 o

MA about; mime E x

Ж "H-NMR (400 MHz, SOzOB) b ppt 2.46 (s, ЗН), 2.47-2.56 (t, 4Н), 3.49 (t, 2Н), 3.56-3, 58 (t, 2H), 3.81-3.83 (t, 2H), 72 4.60 (t, 2H), 4.85 (s, 2H), 6.65-6.68 (t, 1H ), 6.88 (t, 1H), 7.56 (d, 2H), 8.06-8.09 (t, ЗН), 7.96 (s, 1H), 9.46 (s, 1H) o I CM: MANI -488.2

In

X o)

N m- m g; /

Mach M b rrt 2.43 (s, ZN), 3.11 (t, 4H), 3.24 (t, 2H), 3.75 (s, 4H), 79 - Zh 4.55 (t, 2H ), 4.71 (c, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t, y, 1H), 8.00 (c, 1H), 8 .23 (s, 1H), 8.80 (d, 2H), 9.50 (s, 1H). » M ISM5: (MANI -444 5 d

WITH

B o n s u /

Mach M b rrt 1.17 (d, 6H), 2.44 (t, 2H), 3.24 (t, 2H), 3.64 (t, 2H), - 4.21 (d, 2H), 4.55 (t, 2H), 4.70 (d, 2H), 6.70 (d, 1H), 6.88 (d, 74 s-another 1H), 6.96 (d, 1H), 7 .08 (t, 1H), 7.95 (s, 1H), 8.28 (d, 1H),

M p 8.75 (t, 1H), 8.83 (d, 1H), 9.49 (s, 1H). And CM5: shk (MANI -458.6 y

Table 2

Pr. "IN NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 o)

Mel in

М М- b ррт 3.11 (с, ЗН), 3.25 (t, 2Н), 3.66 (t, 2Н), 4.43 (t, 2Н), 75 m 4.56 (t, 2Н ), 4.70 (s, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.06-7.12 (t, ЗН), 7.96 (s, 1H), 8 .08 (d, 2H), 8.76 (c, 1H), 9.50 o (c, 1). SM: MANI -466.1 oi /to / (0)

M

MU s b rrt 3.25 (t, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 5.82 (s, 2H), 76 My 6.62 (d, 1H) , 6.70 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.54 (s,

НМ Ж 1Н), 8.03 (d, 2Н), 9.45 (с, 1). SM: MANI -360.0 i

M

IF)

N

KY b ppt 2.85 (t, AN), 3.15 (t, 4H), 3.23 (t, 2H), 4.54 (t, 2H), 7 Mch t U 4.71 (s, 2H ), 6.79 (d, 1H), 6.88 (d, 1H), 7.06 (t, 1H), 8.01 (s, ho | M-k 1H), 8.12 (s, 1H ), 8.24 (s, 1H), 8.66 (s, 1H), 9.50 (s, 1H). cm: (MANI -429.0

WITH

M

N

(o; m-x M C cha m-K b rrt 3.25 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.72 (d, 1H), 78 is 6.88 (d, 1H), 7.08 (t, 1H), 7.23 (d, 1H), 7.59-7.96 (t, 1H), dk, 8.13 (s, 1H), 8.66 (dd, 1H), 8.93 (s, 1H), 8.99 (d, 1H), 9.52 7 (s, 1). CM: MANI -411.2

AGAIN;

Ha v/o

Table 2

PR. "NMR (400 MHz, OM5O 46)

Mo Structure or otherwise shown/data | CM5 o mech ve

M "H-NMR (500 MHz, OM5O-dv) 5 ppt 2.84 (d, Z H), 3.25 (t,

M 2H), 4.55 (t, 2H), 4.74 (s, 2H), 6.71 (d, 1H), 6.90 (d, 1H), 79 - 7.08 (t, 1H), 8.11 (d, 1H), 8.29 (s, 1H), 8.73 (dd, 1H), 8.81 y, (dd, 1H), 9.00 (s, 1H), 9.49 (d, 1H), 9.54 (s, 1H).). G/CM:

M (Meng-402.4

N -

M

/ about (9) I'm in"

We found 1.88 (d, AN), 3.25 (t, 2H), 3.53 (t, 2H), 3.70 (t, 2H),

M 4.55 (t, 2H), 4.74 (s, 2H), 6.71 (d, 1H), 6.87 (d, 1H), 7.08 (t, seh 1H), 7.85 (d, 1H), 8.26 (s, 1H), 8.69 (k, 1H), 9.43 (d, 1H), m 9.53 (s, 1H). SM: IMEN -442,А 6) c) mor "H-NMR (400 MHz, СозОБ) 5 ppt 2.67-2.70 (t, 4Н), 3.29-vi ok Z, (t, 2Н) , 4.01-4.04 (t, AN), 4.59 (t, 2H), 4.79 (s, 2H),

In 6.69 (d, 1H), 6.93 (t, 1H), 7.09 (t, 1H), 7.86 (s, 1H), 8.11 (d, aa: ny; 1H), 8.68 (c, 1H), 9.42 (c, 1H). (SM: (MeNI-446,2 5. o

Mach SO

Ж "H-NMR (400 MHz, MeOH-а4) 5 ppt 1.54-1.56 (t, 6H), va 2.40 (s, ЗН), 3.27-3.28 (t, 2H) , 4.49-4.53 (t, 4 H), 4.78 (s, that 2 H), 6.69 (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H), 7.76 (s, 1H),

I 8.13 (c, 1H), 9.41 (c, 1H). HOM: (MANI -390.2 m

And vv

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 o

And more

M. m b rrt 2.42 (s, ZN), 3.25 (t, 2H), 4.53-4.58 (t, AN), 4.73 (d, 83 ZK 2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 8.13 (s, 1H),

In 8.43 (d, 1H), 8.93 (t, 1H), 9.05 (d, 1H), 9.52 (s, 1H). And SM:

AH (MNE -403.4

M

/o o) sh ve

Mo M I N NMR (500 MHz, OM5O-av) b rrt 1.41 (d, ZN), 3.25 (t,

UDC 2H), 4.55 (t, 2H), 4.73 (s, 2H), 4.75-4.84 (t, 1H), 5.43 (d, 84 -U 1H), 6.70 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.60 (d, 1H),

I 8.10 (s, 1H), 8.48 (dd, 1H), 8.93 (s, 1H), 9.15 (d, 1H), 9.52 m (s, 1). SM: |MeNI-389.2 pcs but o)

N

MU, in ; b ppt 3.25 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.71 (d, 1H), 85 M: t 6.90 (d, 1H) , 7.08 (t, 1H), 7.50 (dd, 1H), 7.88 (d, 1H), 8.63

E schu (dd, 1H), 9.02 (d, 2H), 9.51 (s, 1). SM: MANI -363.2 sq. m

M c)

Mach 2 IN NMR (400 MHz, OM50O-4v) b ppt 3.00 (t, 2H), 3.22-3.27

Ma im (t, 5H), 3.72 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), - 6.89 (d , 1H), 7.07 (t, 1H), 7.49 (d, 1H), 8.09 (s, 1H), 8.49 y, (dd, 1H), 8.89 (s, 1H) , 9.16 (d, 1H), 9.52 (s, IN). And SM:

M (MANI -403.4

Shk c)

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (c)

Mach M : ; b rprt 2.14 (t, ZN), 2.55 (t, 2H), 3.25 (t, 2H), 3.95 (t, 2H), 87 o Mach M 4.56 (t, 2H) , 4.74 (s, 2H), 6.70 (s, 1H), 6.90 (s, 1H), 7.08 (t, --Ж 1H), 8.15 (s, 1H), 8 .73 (c, 1H), 8.92 (c, 1H), 9.02 (c, 1H), and now 9.53 (c, 13). G CM5: (MANI -428.2.

M

(F)

Mel E

Mach M b rprt 3.15 (s, 6H), 3.41 (s, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 88 -M 6.06 (s, 1H ), 6.70 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.97 (c, i 1H), 9.03 (c, 1H), 9, 50 (p. 13). And CM: MANI -389.2 more

M

(6)

M ve b rrt 2.19 (s, 6H), 2.52-2.54 (t, 2H), 2.78 (t, 2 H), 3.25 (t,

I Mach kt 2H), 4.55 (t, 2H), 4.72 (s, 2H), 6.70 (d, 1 H), 6.90 (d, 1 H),

M -l 7.08 (t, 1 H), 7.21 (d, 1 H), 7.47 (t, Z H), 7.90-8.00 (t, Z H),

Its 8.83 (c, 1 H), 9.51 (c, 1 H). I. SM: MANI -415.2 6)

Mach M uv b rrt 1.44 (s, 6H), 3.26 (t, 2H), 4.19 (s, 2H), 4.56 (t, 2H),

Mach M 4.74 (s, 2H), 6.71 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 8.28 (s,

M -- M 1H), 8.82-9.49 (t, AN), 9.54 (s, 1H). And SM5 (MANI -442.2 x o

M

Table 2

Pr. "IN NMR (400 MHz, OM5O-dv)

Mo Structure or otherwise shown/data | CM5 (9)

M Sho "H-NMR (400 MHz, MeOnH-44) b ppt 2.67-2.70 (t, 4H), v 3.47-3.49 (t, 2H), 4.01-4.04 (t, 4H), 4.59-4.60 (t, 2H), 91 sya and RO 14.80-4.82 (t, 2H), 6.65-6.68 (t, 1H), 6 .88 (t, 1H), 6.94 (d,

M- 1H), 7.90 (s, 1H), 8.10-8.13 (t, 1H), 8.68 (d, 1H), 9.44 (s, 1 m M N.I SM: MANI -464.2

AND

IF)

M Co "H-NMR (400 MHz, MeOnH-44) b ppt 3.40-3.42 (t, 2H), with 3.55-3.58 (t, 4H), 3.82-3.85 (t, 4H), 4.58-4.62 (t, 2H), 92 sya M KO 14.80-4.82 (t, 2H), 6.65-6.68 (t, 1H), 6 .88 (t, 1H), 6.96 (d,

K 1H), 7.91 (s, 1H), 8.14-8.16 (t, 1H), 8.71 (d, 1H), 9.45 (s, 1

As; M N.I SM: MANI -448.2 o. at;

Mel in

Ma. kt E b ppt 3.40 (t, 2H), 4.56 (t, 2H), 4.76 (s, 2H), 6.73 (dd, 1H), 93 M 6.96 (t, 1H) , 8.14 (d, 1H), 8.43 (s, 1H), 8.85 (dd, 1H), 9.06 s, (d, 1H), 9.54 (s, 1H), 9, 56 (d, 1H). SM: (MANI: -388.1 m pc and 4 o

Mach in ; b ppt 3.43 (t, 2H), 4.56 (t, 2H), 4.74 (d, 2H), 6.73 (dd, 1H), 94 M. - E 6.97 (t, 1H ), 7.43 (dd, 2H), 7.45 (d, 1H), 7.85 (t, 2H), 8.84

In (d, 1H), 9.49 (c, 1H). And SM: (MANI -380.0

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 (F)

Me in"

Me M b ppt 3.03 (d, 6H), 3.25 (t, 2H), 4.55 (t, 2H), 4.74 (d, 2H), 95 M 6.70 (d, 1H) , 6.90 (d, 1H), 7.08 (t, 1H), 7.69 (d, 1H), 8.24 (s,

Che 1H), 8.67 (dd, 1H), 9.02 (t, 1H), 9.42 (d, 1H), 9.54 (s, 1H). m SM: Man -4162

X -

M

/ e) (o)

M ve

М М-К b ррт 1.46 (d, ЗН), 1.95-1.99 (t, 1Н), 2.22-2.47 (t, ЗН), their M 3.41 (t, 2Н ), 3.62 (dd, 1H), 3.80 (t, 1H), 4.48 (t, 1H), 4.60 ke, (t, 2H), 4.82 (s, 2H), 6 .69 (d, 1H), 6.93 (d, 1H), 7.12 (t, 1H),

M? 7.40 (d, 1H), 8.13 (5 1H), 8.57 (d, 1H), 8.88 (c, 1H), 9.47 (c, ) 18). SM: MANI -428.2

With Fr

M-- n; AH fa

WHAT should they do 3.23 (t, 2H), 3.57-3.64 (t, 11H), 4.55 (t, 2H), 4.70 (s, 97 pcs 2H), 6.69 ( d, 1H), 6.87 (d, 1H), 6.97 (t, 1H), 7.07 (t, 1H),

M at 7.96 (s, 1H), 8.28 (dd, 1H), 8.76 (s, 1H), 8.85 (d, 1H), 9.50 7 (d, 1H). HOM: (MANI -487.2 x s) o o-4 M o ; b ppt 2.16-2.23 (t, 2H), 3.03 (s, ZN), 3.23 (t, 2H), 3.40 (s,

In My 2H), 4.24 (t, 2H), 4.54 (t, 2H), 4.72 (s, 2H), 6.68 (d, 1H), and in Shui 6.88 (s, 1H), 7.06 (t, 1H), 8.16 (t, 1H), 8.19 (s, 1H), 8.26 (s, o-y 1H), 8.92 (s, 2H) , 9.52 (p. 13). And CM5: IMANI-481,2

M

Table 2

Pr. "NMR (400 MHz, OM5O-sv)

Mo Structure or otherwise shown/data | CM5 (9)

M

MU Z ;

M. pc b ppt 1.48 (s, 6H), 3.25 (t, 2H), 4.55 (t, 2H), 4.72 (s, 2H),

M 5.27 (c, 1H), 6.69 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.73 (d, she: 1H), 8, 09 (s, 1H), 8.45 (t, 1H), 8.88 (s, 1H), 9.13 (s, 1H), m 9.53 (s, 1H). ISM5: (MANI -4031 sh-

IF) o mech M Nu fi b rrt 2.18-2.27 (t, 2H), 2.73 (d, 2H), 2.84 (d, 2H), 2.88-

W 3.00 (t, 4H), 3.24 (t, 2H), 4.55 (t, 2H), 4.72 (s, 2H), 6.70 (d, 100 s 1H), 6, 88 (d, 1H), 7.07 (t, 1H), 7.41 (d, 1H), 8.09 (s, 1H),

M 8.49 (dd, 1H), 8.95 (s, 1H), 9.16 (d, 1H), 9.54 (s, 1H). k cm: (Man -478.2

IS

J

6) m-x M Tu cha x-K b rrt 1.42 (s, 6H), 3.24 (t, 2H), 4.16 (s, 2H), 4.55 (t, 2H), 101 Another 4.74 (s, 2H), 6.69 (d, 1H), 6.89 (d, 1H), 7.07 (t, 1H), 8.05 (d, t, 1H), 8, 29 (c, 1H), 8.70 (dd, 1H), 9.41 (d, 1H), 9.53 (c, 1H), m 10.23 (c, 1). And SM: (M-ANI-442,0. 7

Mi ho; () m-x M y;

M. M-K b rrt 2.04 (s, ZN), 2.41 (s, ZN), 2.52 (t, 2H), 3.03 (s, ZN), that is 3.25 (t, 2H), 3.50 (t, 2H), 4.55 (t, 2H), 4.73 (d, 2H), 6.70 102 - xx, (d, 1H), 6.89 (d, 1H ), 7.08 (t, 1H), 7.66 (dd, 1H), 8.24 (d,

M, 1H), 8.66 (dd, 1H), 9.04 (t, 1H), 9.42-9.44 (t, 1H), 9.56 (s, and 7 1). 1 CM: (MANI -473.0 ut -m () y

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5

Gee)

M in

M: dk b ppt 1.87 (dd, 4H), 2.48 (s, ЗН), 3.24 (t, 2H), 3.53 (t, 4H), 103 Ж 4.55 (t, 2H ), 4.69 (s, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.90 (s, 1H), 8.03 (d, 1H), 8.65 (d, 1H), 8.72 (s, 1H),

M X 9.48 (s, 1H). SM: MANI -428.4 pcs s (in)

Mel in

M. M - Zh b ppt 2.46 (s, 2H), 3.24 (t, 2H), 3.80 (t, 2H), 4.09 (s, 2H), 104 sh- 4.55 (t, 2H), 4.70 (d, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.06-

M 7.09 (t, 2H), 8.03 (s, 1H), 8.19 (s, 1H), 8.48 (d, 1H), 8.82 and (d, 1H), 8.90 (d, 1H), 9.50 (c, 1H). SM: MANI: -443.1 what (in)

IF)

Me re"

M. sh u b rrt 2.44 (s, ZN), 3.24 (t, 4H), 3.45 (t, 2H), 3.74 (s, 2H), 105 u, 4.55 (t , 2H), 4.70 (s, 2H), 6.71 (d, 1H), 6.88 (d, 1H), 7.09 (t, x M 1H), 7.90 (s, 1H) , 8.02 (c, 1H), 8.27 (d, 1H), 8.80 (d, 1H), n, 8.84 (c, 1H), 9.51 (c, 1). G SEM5: IMANI-457 2

C is not (F)

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 6)

Ge) Mach CO b rrt 3.10 (s, ZN), 3.24 (s, 2H), 3.69 (s, 2H), 4.51-4.56 (t, 106 Sho) Mach M AN) , 4.72 (s, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.06 (dd, 1H), sho - 8.16-8.23 (t, 2H ), 8.40 (s, 1H), 8.99 (s, 1H), 9.52 (s, 1H).

And SM5: (MANI -466.9 0-X X

M

(o) m c

Mach M b rrt 2.40-2.48 (t, AN), 2.74 (t, 2H), 2.96 (t, 2H), 3.25 (t, -M 2H), 3.43- 3.47 (t, 4H), 4.55 (t, 2H), 4.72 (s, 2H), 6.70 (d, 107 ka 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.41 (d, 1H), 8.00 (s, 1H),

X 8.09 (c, 1H), 8.40 (dd, 1H), 8.91 (bromine, 1H), 9.16 (d, 1H), already; 9.51 (c, 1). GSM5: MANI -485.2 o. ge) meh vo

Mach Co b rrit 1.98 (s, ZN), 2.49-2.47 (t, AN), 2.72 (t, 2H), 2.95 (t, ve 2H), 3.25 (t , 2H), 3.47-3.44 (t, 4H), 4.55 (t, 2H), 4.72 (s, 108 in 2H), 6.70 (d, 1H), 6.89 ( d, 1H), 7.08 (t, 1H), 7.41 (d, 1H), 7 8.09 (s, 1H), 8.40 (dd, 1H), 8.91 (bromine, 1H) , 9.16 (d, 1H), ac 9.51 (c, 13). G SMm5: IM--NI-499.2 sv o west U

Me Co b ppt 2.63 (t, 2H), 2.77 (t, 2H), 2.94-3.00 (t, 4H), 3.14 (t, pk, 2H), 3.25 ( t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 109 g x 6.89 (d, 1H), 7.08 (t, 1H), 7.41 (d, 1H), 7.74 (s, 1H), 8.10 (s, c 1H), 8.41 (dd, 1H), 8.91 (bromine, 1H), 9 .17 (d, 1H), 9.51 (s, mk 18). . CMm5: (MANI -471.4 nu s)

Table 2

Pr. IN NMR (400 MHz, OM5O-dv)

Mo Structure or otherwise shown/data SCM5 o

MU about

We b rpt 2.44 (t, 2H), 2.50 (t, 2H), 3.42 (t, 2H), 3.45 (t, 2H), shui 3.54-3.57 (t, 6H), 4.47 (t, 1H), 4.55 (t, 2H), 4.70 (d, 2H), 110 M 6.70 (d, 1H), 6.87 (d, 1H), 6.94 (d, 1H), 7.07 (t, 1H), 7.94 (s,

A 1H), 8.25 (dd, 1H), 8.74 (bromine, 1H), 8.82 (d, 1H), 9.49 (c, ac 1). cm: (MANI -473.2

And but (oh)

N

M- S cha M b rrt 2.82 (d, ZN), 3.24 (t, 2H), 4.55 (t, 2H), 4.69 (s, 2H), 113 M 6.45 (d , 1H), 6.70 (d, 1H), 6.87-6.95 (t, 2H), 7.07 (t, 1H), po, 7.66 (s, 1H), 8.49 ( d, 1H), 8.78 (c, 1H), 9.47 (c, 1H). And CM5: se IMANI-392.0

Customs

M

N u

N cha M b rrt 3.08 (s, 6H), 3.24 (t, 2H), 4.55 (t, 2H), 4.70 (d, 2H), 112 is 6.61 (d, 1H ), 6.70 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.68 (s, o 1H), 8.51 (d, 1H), 8, 81 (c, 1H), 9.47 (c, 1H). CM5: se IMANI-406,2

MO ItTE

M

H

(o) y, o ; b ppt 1.79-1.80 (t, 2H), 3.24 (t, 2H), 3.46 (t, 2H), 3.58 (t, xEUd 2H), 3.68-3.76 (t, 2H), 3.81-3.89 (t, 2H), 4.55 (t, 2H), 4.70 113 shii (s, 2H), 6.70 (d, 1H), 6, 82 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), and 7.82 (s, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.21-8.24 (t, 1H), xg 8.71 (s, 1H), 8.80 (dd, 1H), 9.49 (s, 1H). SM5: p IMANI-471.2 ohm /

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5

IF) m

Ma. M b ppt 1.15 (t, ЗН), 3.25 (t, 2H), 3.47 (t, 2H), 4.55 (t, 2H), 114 M 4.74 (s, 2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.07 (t, 1H), 8.12 (d, x 1H), 8.28 (s, 1H), 8.75 ( dd, 1H), 8.83 (t, 2H), 9.48 (a. 1H),

M XM 9.55 (p, 1). CM: (MANI -416.0

N shi

M

-Y (F) (F;

N

Mach E b rrt 3.13 (t, 2H), 4.54 (t, 2H), 4.75 (s, 2H), 6.71 (dd, 1H), 115 M.Yu M E 6.96 ( t, 1H), 7.49 (d, 1H), 7.95 (s, 1H), 8.25 (t, 1H), 8.51 (Id,

E M 1H), 8.89 (s, 1H), 9.49 (s, 1H). I EM5: (MANI -381.0 pcs m pcs (6)

Mach M I b rrt 2.51 (t, ZN), 3.29 (t, 2H), 4.54 (t, 2H), 4.74 (s, 2H), 116 Maiu sh- E 6.70 ( dd, 1H), 6.95 (t, 1H), 7.99 (d, 1H), 8.10 (s, 1H), 8.43

M (s, 1H), 8.47 (d, 1H), 8.94 (s, 1H), 9.51 (s, 1H). I SM5: c, IMANI-376.9 ac

M-- );

M. E

M M b ppt 3.23 (t, 2H), 4.22 (t, 2H), 4.48 (t, 2H), 4.54 (t, AN), 117 --M 4.71 (s, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.06 (t, 1H), 8.09 (s, g 1H), 8.15 (d, 1H), 8 .54 (dd, 1H), 8.90 (s, 1H), 9.10 (s, 1H), o m 9.51 (s, 13); See: (MANI -430.2

Hmm oh

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (F);

N

Mach E b rrt 2.24 (s, ЗН), 3.44 (t, 2H), 4.56 (t, 2H), 4.73 (s, 2H), 118 M:yu - E 6.73 ( dd, 1H), 6.96 (t, 1H), 7.48 (d, 1H), 7.67 (s, 1H), 8.48

M (t, 2H), 9.48 (s, 13). SM: (MANI: -377.2 units of housing

M

(F)

M M I N NMR (400 MHz, meon-av4) b rrt 1.04 (dt, 2H), 1.09 (dt, with ZN), 2.22 (s, AN), 3.41 (t, 2H), 4.60 (t, 2H), 4.84 (d, ЗН), 119 | ME 6.67 (dd, 1H), 6.88 (dd, 1H), 7.45 (d, 9U -8.3 Hz, 1H), 8.01 (s, y: (y; 1H), 8.25 (dd, 1H), 8.94 (d, 1H), 9.46 (s, 1H). I CM5: m М-М IMANI-403,2 (c)

N

M Sho in IN NMR (400 MHz, meon-a4) b ppt 3.41 (t, 2H), 3.55-3.59 120 dJ ME (t, 4H), 3.83-3.87 (t, 4H), 4.61 (t, 2H), 4.86 (s, 2H), 6.67

Its 7 (dd, 1H), 6.84-6.91 (t, 1H), 7.40 (dd, 1H), 7.62 (d, 1H),

M MM 8.17-8.21 (t, 2H), 9.46 (s, 1H). SM: (MANI: -448.0 s (F) ()

M-ve b ppt 3.42 (d, 2H), 4.56 (t, 2H), 4.71 (d, 2H), 6.73 (dd, 1H), 194 M / M M 6.92- 7.01 (t, 1H), 7.24 (d, 1H), 7.45 (Id, 1H), 7.49-7.57 (t,

M Mu ho E 2H), 7.59 (s, 1H), 7.65 (dd, 1H), 7.76 (s, 1H), 8.65 (s, 1H), - F 9.45 (s , 1). SM: (MANI -387.0

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 (F) nm. o M M I N NMR (400 MHz, meon-a4) b rprt 3.41 (d, ЗН), 4.61 (t, 122 2 vyy 2H), 4.87 (d, 2H), 5.52 (c, 1H), 6.68 (dd, 1H), 6.86-6.95 (t,

ME 1H), 7.56-7.65 (t, 2H), 7.78-7.88 (t, 2H), 7.90-7.97 (t, (y; 2H), 9.47 (c, 1). CM: MANI -405.0

M-M (F)

M- CO I"H NMR (400 MHz, Mmeon-a4) b ppt 2.49 (s, ZN), 3.44-3.46 123 cha m-K (t, 2H), 4.60 (t, 2H), 4.82 (s, 2H), 6.70 (d, 1H), 6.95 (d, 1H),

TM 7.12 (t, 1H), 7.41 (s, 1H), 7.70 (s, 1H), 7.85 (dd, 1H), 8.51 - (dd, 1H), 9.44 (c, 13) CM: MANI -359.0 m pcs (c)

M M b ppt 3.42 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (dd, 1H), 124 | 5 6.96 (t, 1H), 7.73 (d, 1H), 7.79 (s, 1H), 8.59 (d, 1H), 8.72 (d, s ME 2H), 9 ,49 (p, 1). SM: MANI -397 1

I i i si M 6) hu o

M xx shko b rrt 3.05 (t, 2H), 3.25 (t, 2H), 3.47 (s, 2H), 3.89 (t, 2H), 125 - M 4.55 (t, 2H), 4.72 (c, 2H), 6.69 (d, 1H), 6.89 (d, 1H), 7.07 (t, by 1H), 7.95 (d, 1H), 8 .13 (s, 1H), 8.50 (dd, 1H), 9.08 (s, 1H),

He) M y, 9.17 (s, 1H), 9.53 (s, 13). EM: MANI -443.2 no

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5

IF) zh o

Ma i b rprt 3.24 (t, 2H), 3.71 (k, 2H), 4.20 (t, 2H), 4.53-4.61 (t, 126 - U ZN), 4.70 (d, 2H), 5.69 (d, 1H), 6.50 (d, 1H), 6.69 (d, 1H),

M X 6.86 (d, 1H), 7.07 (t, 1H), 7.91 (s, 1H), 8.21 (dd, 1H), 8.74- - 8.76 (t, 2H ), 9.49 (c, 1). And CM5: IMANI -416.2 ry, but (F)

Me in"

Mach i R b rrt 2.41 (s, ZN), 3.45 (t, 5H), 4.56 (t, 2H), 4.74 (s, 2H), 127 - M 6.73 (dd, 1H), 6.96 (t, 1H), 7.79 (s, 1H), 8.08 (s, 1H), 8.72 po (d, 2H), 9.51 (s, 1). G сM5: MANI: -455.1 he ) M

VH oo (F)

M in

M: - E b ppt 2.43 (s, ЗН), 3.28 (s, ЗН), 3.45 (t, 2Н), 4.57 (t, 2Н), 128 M 4.73 (t, 2H), 6.73 (dd, 1H), 6.98 (t, 1H), 7.63 (d, 1H), 7.68 sh: (c, 1H), 7.82 (dd, 1H), 7.91 (s, 1H), 8.79 (s, 1H), 9.49 (s, 18). CMm5: (MANI: -454.1 heh

VH oo

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (6)

Nn

Mach v

Ma rob ppt 1.87 (t, 4H), 3.44 (t, 2H), 3.53 (t, 2H), 3.68 (dd, 2H), 129 M 4.56 (t, 2H), 4.74 (c, 2H), 6.73 (dd, 1H), 6.96 (t, 1H), 7.84 y, y (d, 1H), 8.29 (c, 1H), 8, 69 (dd, 1H), 8.90 (s, 1H), 9.46 (d, their M 1H), 9.53 (s, 1). HOM: MANI -460.2 ha)

IF)

N

Me ve

M. ME /b ppt 1.83-1.88 (t, 4H), 2.41 (s, ZN), 3.23 (t, 2H), 3.54 (t, 130 M 2H), 3 .67 (t, 2H), 4.57 (t, 2H), 4.14 (d, 2H), 6.73 (dd, 1H), - She 6.98 (t, 1H), 7.71 ( s, 1H), 7.73 (s, 1H), 8.52 (s, 1H), 8.81 (s, 1H), 9.49 (s, 1). HOM: (MANI -474.1 and M M (in) (F)

N

Me o

ММЕ |b ppt 2.40 (s, ZN), 3.03 (d, 6H), 3.47 (t, 2H), 4.57 (t, 2H), 181 M 4.73 (s, 2H), 6.74 (dd, 1H), 6.98 (t, 1H), 7.55 (s, 1H), 7.73 sh: (s, 1H), 8.50 (s, 1H), 8.81 (c, 1H), 9.50 (c, 1H). And CM5:

She IMANI-448,2 her,

M M

/ (F) (9) m

М M- Е b ррт 2.07 (с, ЗН), 2.15 (с, ЗН), 3.42 (t, 2Н), 3.72 (с, ЗН), 132 B | 4.58 (t, 2H), 4.70 (d, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.47 sh-M (s, 1H), 8, 54 (t, 1H), 9.43 (p, 13). CM: IMANI-394.2 m

M

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 in

N

/

M de: co b pprt 2.64 (t, 2H), 3.02 (s, 2H), 3.18 (s, 2H), 3.25 (t, 2H), - UM 3.72 (s, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 6.89 (d, 133 and 1H), 7.07 (t, 1H), 7.54 (d, 1H), 7.79 (s, 1H), 8.13 (s, 1H),

M X 8.51 (dd, 1H), 8.93 (s, 1H), 9.21 (a. 1H), 9.52 (s, 1H). ex I SmM5: MANI -457.2

IN

M no

N

1F)

N

M- M i; /

M

M xx i b rrt 3.24 (t, 2H), 3.50-3.62 (t, 8H), 4.55 (t, 2H), 4.68 (s, 134 sho M 2H), 6, 68 (d, 1H), 6.88 (d, 1H), 7.00-7.08 (d, 1H), 7.94 (s, ke 1H), 8.12 (s, 1H), 8, 28 (d, 1H), 8.85 (s, 1H), 9.44 (s, 1H). and 7 CM: MANI -457 2

WITH

Gee)

N ; in

M M

Ma M b ppt 2.76-2.82 (t, 5H), 2.98-3.02 (t, 5H), 3.22 (t, 2H), 135 - M 4.55 (t, 2H) , 4.72 (c, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.08 (t, pe 1H), 7.49 (d, 1H), 8.08 (c, 1H), 8.47 (dd, 1H), 8.91 (c, 1H), and M y, 9.14 (d, 1H), 9.51 (c, 1H). SM: MANI -444.0

M

/ s) (F)

N

M.O.M b ppt 3.43 (t, 2H), 4.56 (t, 2H), 4.76 (s, 2H), 6.73 (dd, 1H), 136 | in 6.96 (t, 1H), 8.16 (d, 1H), 8.41 (s, 1H), 8.96 (dd, 1H), 9.05

MME (s, 1H), 9.54 (d, 2H). And SM5: MANI -431.1 to her - M-M

SEz

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 (F)

N

Mach M S /

М. ), 4.72 (s, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.08 (t,

Che: 1H), 8.08 (s, 1H), 8.41 (d, 1H), 8.90 (t, 1H), 9.03 (d, 1H),

M X 9.51 (p. 13). G CMm5: (MANI -403.2 sho (in)

H

(F)

N

Mach in;

M. ME b rprt 3.46 (t, 2H), 3.94 (s, ЗН), 4.57 (t, 2H), 4.72 (s, 2H), 138 im 6.74 (dd, 1H), 6.97 (t, 1H), 7.19 (s, 1H), 7.69 (s, 1H), 8.41 rain (s, 1H), 8.82 (bromine, 1H), 9 ,48 (p, 1). And SM: MANI: -427.0

M - wild to (F)

N

Me po;

M - E b ppt 2.54 (s, ZN), 3.24-3.44 (t, 5H), 4.56 (t, 2H), 4.74 (s, 139 M 2H), 6.72 (dd, 1H), 6.98 (t, 1H), 7.78 (s, 1H), 7.98 (d, 1H), ше: 8.14 (d, 1H), 8.87 (s, 1H), 9.51 (s, 1H). I. SM5: m IMANI-454.9 in x r

VH oo

Table 2

Pr. "H NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 (o;

Me in

I have ME b rrt 2.50 (s, 2H), 2.54 (s, 2H), 3.43 (t, 2H), 4.56 (t, 2H), 140 M 4.74 (s, 2H ), 6.73 (dd, 1H), 6.96 (t, 1H), 7.78 (s, 1H), 7.99 and: (d, 1H), 8.14 (d, 1H), 8 .87 (c, 1H), 9.50 (c, 1H). (CM: m (MANI -434.1

X sh-

M

/ s) (o)

H "H NMR (400 MHz, MeOn-a4) b ppt 3.48 (t, 2H), 3.92 (s, 143 o7 M. IM ZN), 4.56-4.60 (t, 2H), 4.82 (s, 2H), 6.62-6.68 (t, 1H), 6.87

Che (dd, 1H), 7.08 (dd, 1H), 7.89 (s, 1H), 8.00 (dd, 1H), 8.18 cha ME (dd, 1H), 9.40 (s, 1). CM: MANI -393.0

Her 17 xx M-M (o)

M

In s "H NMR (400 MHz, MeOn-av4) b ppt 3.44-3.40 (t, 2H), 142 Mach and E 13.95 (s, ЗН), 4.58 (d, 2H), 4.81 (c, 2H), 6.64 (dd, 1H), 6.85 - UM (t, 1H), 6.91 (d, 1H), 7.92 (c, 1H), 8.21 (dd, 1H), 8.68 (d, 1H), 9.42 (s, 1). CM: (MANI: -393.0 /4 m

Sho

-o (c) b ррт 1.44 (t, 9-7.18 Hz, ЗН) 3.29-3.48 (t, 2Н) 4.17 (k, а М 9-7.15 Hz, 2Н ) 4.60 (t, 9U-8.72 Hz, 2H) 4.76 (s, 2H) 6.40- 143 M 6.50 (t, 1H) 6.75 (dd, 4-8.63, 3.80 Hz, 1H) 7.00 (t, 9U-9.44

We are E

M Hz, 1H) 7.55-7.62 (t, 1H) 7.72 (s, 1H) 9.44 (s, 1). And SM:

In the United States - (MANE-379.9

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | СМ5 e) ppt 1.41-1.49 (t, 6Н), 3.49 (t, 2Н), 4.40-4.49 (t, 1Н), m- mM 4.56 (t, -8 ,8Hz, 2H), 4.72 (s, 2H), 6.46 (d, 9-1.8 Hz, 1H), 144 M m-K E 6.73 (dd, 9-8.7, 3 .9 Hz, 1H), 6.93-7.01 (t, 1H), 7.57 (d,

And they have 9-1.5 Hz, 1H), 7.68 (s, 1H), 9.48 (s, 13). And SM: s- (MANI -394.0

M t) o)

M in

M. sh- E 5 ppt 3.41 (t, 2H), 3.89 (s, ЗН), 4.55 (t, 2H), 4.75 (s, 2H), 145 M 6.71 (k , 1H), 6.96 (t, 1H), 7.77 (t, 2H), 8.21 (t, 1H), 8.47 (s, weight 1H), 8.97 (s, 1H) , 9.51 (p. 18). GSM5: (MANI -393.2

J

M-- lo o

H IN NMR (400 MHz, Meon-44) 5 ppt 3.48 (t, 2H), 4.58 (19,

MM 2H), 4.82 (s, 2H), 6.65 (dd, 1H), 6.81-6.89 (t, 1H), 7.45- 146 | KI and 7.9 (t, 2H), 7.55 (dad, 2H), 7.61-7.66 (t, 2H), 7.91-7.95

As; (t, 2H), 7.97 (s, 1H), 9.43 (s, 1H). SM: |(M--NO):

M-k Man -429.9 si si o)

N as Ve

M m i 5 ppt 3.25 (t, 2H), 3.88 (s, ЗН), 4.54 (t, 2H), 4.67 (s, 2H), 147 in: 6.70 (d, 1H), 6.95 (t, 1H), 8.04 (s, 1H), 8.12 (s, 1H), 8.44 (s, -UM 1H), 8.54 (s, 1H), 9.46 (c, 1H). SM: (MANI -366.1 m

M

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5

IF)

M in

M. ME b rrt 1.50 (d, 6H), 3.40 (t, 2H), 4.55 (t, 2H), 4.71 (s, ZN), 148 them 6.72 (dd, 1H), 6.97 (t, 1H), 7.67 (s, 1H), 8.50 (s, 1H), 8.73

SEZ s (s, 1H), 9.48 (s, 1H). And SM: (MANI -462.0 m

UNTIL

(c) in b ppt 1.00-1.09 (t, 4H), 3.23 (t, 2H), 3.81 (dd, 1H), 4.54 149 | M (t, 2H), 4.68 (d, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t, 1H),

M Y " y; 8.01 (s, 1H), 8.13 (s, 1H), 8.48 (s, 1H), 8.67 (s, 1H), 9.47 (s,

M M-M 1). SmM5: (MANI -374.2 (F)

N and b rrpt 0.97-1.09 (t, 4H), 3.40 (t, 2H), 3.79-3.83 (t, 1H), 150 | ME 4.54 (t, 2H), 4.70 (s, 2H), 6.71 (dd, 1H), 6.95 (t, 1H), 8.05 m Y x y; (c, 1H), 8.14 (c, 1H), 8.48 (c, 1H), 8.56 (d, 1H), 9.46 (c, 1H).

M M-K SM: IMeANI-3922 e; n- SO

MME b rrt 1.49 (d, 6H), 2.08 (s, ЗН), 2.16 (s, ЗН), 3.46 (t, 2Н), 151 ve i 4.48-4, 58 (t, ЗН), 4.70 (d, 2Н), 6.74 (dd, 1Н), 6.99 (t, 1Н), шщ- M 7.49 (с, 1Н), 8.54 ( t, 1H), 9.44 (p, 13). And CM5: NAMES -422.2

M

M

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 o)

Me o 5 ppt 3.25 (t, 2H), 3.83 (s, ЗН), 4.56 (t, 2H), 4.72 (d, 2H), 152 M. M 6.51 (d, 1H), 6.71 (d, 1H), 6.90 (d, 1H), 7.09 (t, 1H), 7.51 (s, and Ko 1H), 7.75 (s, 1H), 8.98 (d, 1H), 9.50 (c, 1H). And SM: x -Y (MAN -348.2

M m )

M M in 5 ppt 1.49 (d, 6H), 2.08 (s, ZN), 2.16 (s, ZN), 3.25 (t, 2H), 153 Mach M 4.46-4, 57 (t, ZN), 4.69 (s, 2H), 6.71 (d, 1H), 6.91 (d, 1H),

M 7.10 (t, 1H), 7.45 (s, 1H), 8.66 (s, 1H), 9.45 (s, 13). And SM: ee: (MANE-4042

M.

M

)

Mel in

Mach kt 5 rpt 3.25 (t, 2H), 4.55 (t, 2H), 4.74 (d, 2H), 6.70 (d, 1H), 154 schu 6.88 (t, 1H) , 7.02-7.16 (t, 2H), 7.81 (d, 1H), 8.27 (s, 1H), 8.77 (dd, 1H), 9.05 (t, 1H), 9.41 (y. 1H), 9.54 (c, 1H). m cm: (Man -395.1 aa

IS

E o still mch I"N NMR (400 MHz, MeOn-44) 5 ppt 2.45 (s, ZN), 3.46-3.42 155 Mach z RO Yist, 2n), 3.94 (s, AN ), 4.57 (d, 2H), 4.81 (s, 2H), 6.62-6.67

F (t, 1H), 6.68-6.74 (t, 1H), 6.87 (t, 1H), 7.62 (d, 2H), 9.41 (s, YAN). GSsM5: (MANI: -407.0 /y m

Sho

-at

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (F)

N

Mach ve

M. MEIN NMR (400 MHz, meon-a4) b ppt 2.25 (s, ZN), 3.46-3.41

X (t, 2H), 4.58 (t, 2H), 4.80 (s, 2H), 6.52 (d, 1H), 6.65 (dd, 156 M - 1H), 6.83- 6.89 (t, 1H), 7.43 (d, 1H), 7.60 (s, 1H), 9.29 (s,

M 1). Sm5: MANI -392.0 and 7

YUM

(at);

Me M ) | NMR NMR (400 MHz, meon-av4) b ppt 3.49 (t, 2H), 4.58 (t, 157 M.:yu ME 2H), 4.82 (s, 2H), 6, 65 (dd, 1H), 6.86 (d, 1H), 7.20 (id, 2.9

SI M Hz, 2H), 7.40 (dd, 1H), 7.56 (dd, 1H), 7.71 (s, 1H), 7.90-7.96

SHE: (t, 1H), 9.41 (p, 13). SM: (MANI -414.0

IS

(is,;

Mel in

M сх - Е b ррт 2.08 (с, ЗН), 2.18 (с, ЗН), 3.41 (t, 2Н), 3.73 (dd, ЗН), 158 M 4.06 (t, 2H), 4.56 (t, 2H), 4.70 (d, 2H), 4.93 (t, 1H), 6.74

SHE: (dd, 1H), 6.99 (t, 1H), 7.47 (s, 1H), 8.55 (s, 1H), 9.44 (s,

M X 18). CMm5: (MANI -424.2

In, but (0)

MA 2 b ppt 2.08 (s, ZN), 2.16 (s, ZN), 3.26 (s, ZN), 3.41 (t, 2H), 159 Ma ME 13.69 (t, 2H), 4.18 (t, 2H), 4.58 (t, 2H), 4.70 (d, 1H), 6.74 - Ж (dd, 1H), 6.99 (t, 1H), 7.48 (s, 1H), 8.55 (t, 1H), 9.43 (s,

M - 1). See: IM-ANI-438.2 o m.

M

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | СМ5 (Ф) m. g b ррт 3.43 (t, 2H), 4.57 (t, 2H), 4.77 (s, 2H), 6.72 (dd, 1H), 160 s ME 6 .97 (t, 1H), 8.02 (d, 1H), 8.48 (s, 1H), 8.89 (d, 1H), 9.02 (s,

E | Ts u; 1H), 9.50 (c, 1H), 9.54 (c, 1). SM: (MANI -431.2 4 -M

M u: (F)

Me in

M. ME b rprt 3.40-3.43 (t, 2H), 3.94 (s, ZN), 4.57 (t, 2H), 4.73 (s, 161 im 2H), 6, 73 (dd, 1H), 6.92-6.99 (t, 2H), 7.80 (s, 1H), 8.58 (d, oh 1H), 8.82 (s, 1H), 9, 48 (p. 1). And SM5: (MANI -411.2

M -

M ItTE to (F)

M M b ppt 3.28 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (t, 1H), 162 | in 6.97 (t, 1H), 7.71 (d, 1H), 7.88 (s, 1H), 8.61 (d, 1H), 8.78 (s,

ME 1H), 8.97 (s, 1H), 9.50 (s, 1). And SM: (MANI: -397.1 7

M M-- to si M o

M ve b rrt 2.25 (s, ZN), 3.44 (d, 2H), 4.56 (t, 2H), 4.73 (s, 2H), 163 / M M 6.73 (dd, 1H), 6.96 (t, 1H), 7.42 (d, 1H), 7.71 (s, 1H), 8.47

M xx t E (d, 1H), 8.53 (s, 1H), 8.81 (s, 1H), 9.49 (s, 13). And CM5: - In (MANK-377,1 ac

M--

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5 he)

Mach M Io I"H NMR (400 MHz, Meon-4a4) 5 ppt 2.42 (d, ЗН), 3.44 (t, 164 М. МЕ 2Н), 4.62 (t, 2Н), 4 .85 (c, ZN), 6.63-6.74 (t, 1H), 6.90 (t,

M 1H), 7.04 (d, 1H), 7.73 (d, 1H), 7.94 (t, 1H), 9.46 (d, 1H). ka ISsM8: (MH -395.0 -

M

7

eh)

Mach M IV "H NMR (400 MHz, Meon-44) 5 ppt 2.25 (s, ZN), 3.43 (t, 165 M. ME 2H), 4.63 (d, 2H), 4, 84 (c, 2H), 6.69 (dd, 1H), 6.90 (t, 1H),

M 7.04 (t, 1H), 7.12 (dd, 1H), 7.46 (dd, 1H), 7.64 (s, 1H), 9.44

She: (c, YAN). SM: (MANI -394.0

Oh)

H IN NMR (400 MHz, Meon-44) 5 ppt 3.42 (t, 2H), 4.62 (id, 166 SE m. M 2H), 4.87 (d, ЗН), 6.66-6 .72 (t, 1H), 6.91 (t, 1H), 7.70 (s, with TN), 7.79 (dd, 1H), 8.09 (d, 1H), 8.80 (d , 1H), 9.46 (d, 1H). xx i y E I SM: (MN -431.1 /

M--

M M o;

N

I have 5 ppt 2.45 (s, ЗН), 2.44 (s, ЗН), 3.41 (t, 2Н), 4.56 (t, 2Н), 167 Mohs t E 4.72 (s, 2Н) , 6.73 (dd, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.62

F (d, 2H), 8.70 (c, 1H), 9.47 (c, 1). SM: MANI -391.1 m pcs

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5

F)

E E M M b rprt 3.47 (t, 2H), 4.57 (t, 2H), 4.73 (s, 2H), 6.72-7.06 (t, 168 g ZN), 7, 64 (c, 1H), 7.71 (dd, 1H), 8.03 (d, 1H), 8.78 (d, 2H),

ME 8.83 (d, 2H), 9.49 (c, 1H). And SM: (MANI -413.2

M

Her y7 xx M-M (9)

Mach M I b rrt 3.42 (t, 2H), 3.83 (s, ЗН), 4.56 (t, 2H), 4.73 (d, 2H), 169 M. - E 6.52 ( d, 1H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.51 (d, 1H), 7.78 (s, 1H), 8.87 (d, 1H), 9.49 (c, 1H). SM: (MANI -366.2 cha,

M m (F)

M- ve / M M b rrt 3.40 (t, 2H), 4.02 (s, ЗН), 4.55 (t, 2H), 4.71 (d, 2H), 170 Mu i P 6, 72 (d, 1H), 6.97 (t, 1H), 7.67 (s, 1H), 8.47 (s, 1H), 8.73 (d,

SEZ - M 1H), 9.48 (s, 1H). SM: (MANI -434.1

M

M

/ o

Mel in

Mach M E 16 ppt 1.93 (s, ZN), 3.42 (t, 2H), 4.42 (d, 2H), 4.55 (t, 2H), 171 - 4.74 (s, 2H ), 6.72 (dd, 2H), 6.97 (t, 1H), 7.48 (s, 1H), 8.19 y (s, 1H), 8.55 (d, 2H), 8, 87 (c, 1H), 9.26 (c, 1H), 9.52 (c, 1H). ts MI SM: (Man -434.4

M school

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 (F)

M vo cha M-K E b rrt 2.47 (s, ЗН), 3.29 (t, 2Н), 3.82 (s, ЗН), 4.56 (t, 2Н), 172 | 4.70 (c, 2H), 6.71 (dd, 1H), 6.97 (t, 1H), 7.62 (c, 1H), 7.76 - U (c, 1H), 8.53 (c, 1H), 9.45 (c, 1H). And cMm5: MANI -380.2 "sh)

M

/ (F)

M in

M. ME b rrp 0.93-1.03 (t, AN), 2.09-2.13 (t, 1H), 2.19 (s, ZN), 173 M 3.43 (t, 2H ), 4.55 (t, 2H), 4.71 (d, 2H), 6.72 (k, 1H), 6.96 (t, su 1H), 7.27 (c, 1H), 7, 61 (s, 1H), 8.28 (s, 1H), 8.709 (t, 1H), and X 9.46 (s, 1H). And EM5: (MANI -417.4

M

(F)

M in

M. ME b rprt 3.41 (t, 2H), 3.98 (s, ЗН), 4.55 (t, 2H), 4.74 (s, 2H), 174 im 6.71 (k, 1H), 6.96 (t, 1H), 8.17 (s, 1H), 8.84 (s, 1H), 9.40 (s, -- 2H), 9.51 (s, 1). SM: MANI -394 2

WITH

(F) more / M M b rrt 2.46 (s, ZN), 3.27 (s, 2H), 3.96 (s, ZN), 4.56 (t, 2H), 175 Mach w E 4 .71 (c, 2H), 6.72 (dd, 1H), 6.98 (t, 1H), 7.66 (c, 1H), 8.50 - M (c, 1H), 8.79 ( p, 1H), 9.43 (p, 13). G cM5: MANI -408.2

Hu

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5 NSSYA (0)

N ke s / b rrt 2.45 (s, ZN), 3.26 (t, 2H), 4.57 (t, 2H), 4.74 (s, 2H), 176 Mach ZE 6.72 ( dd, 1H), 6.97 (t, 1H), 7.77 (s, 1H), 8.74 (s, 1H), 9.09 a (s, 1H), 9.50 (s, 13) . GoM5: (MANI -378.2 7 m em (o);

М-х ве b ррт 2.14 (с, ЗН), 2.51 (с, ЗН), 3.40 (t, 2Н), 4.54 (t, 2Н), 177 / М М 4.69 ( s, 2H), 6.68 (k, 1H), 6.94 (t, 1H), 7.72 (d, 1H), 7.58 (s,

Mu i E 1H), 8.27 (d, 1H), 8.81 (c, 1H), 9.41 (c, 1). And CM5: - M (MANI -391.2 ac

M-- (o)

Me in"

M. ME b rprt 2.44 (s, ZN), 3.43 (d, 2H), 4.64 (s, 2H), 4.85 (d, 2H), 178 M 6.71 (d, 1H), 6.93 (d, 1H), 7.58 (d, 1H), 7.70 (d, 1H), 7.74 (c, c, 1H)U, 7.77 (c, 1H) , 9.48 (c, 1H). SM: MANI -401.0 /Й 4 (о) m- vo; cha ME b rrt 0.97-1.04 (t, 4H), 2.04 (s, ZN), 2.24 (s, ZN), 3.48-179 is 3.51 (t, ZN) , 4.55 (t, 2H), 4.68 (d, 2H), 6.72 (t, 1H), 6.95 (t, s 1H)U, 7.47 (s, 1H), 8, 54 (t, 1H), 9.42 (s, 1H). I CM5: / IMaANI-4204

M,

AND

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 6)

N

In B b rrt 2.17 (s, ZN), 3.43 (t, 2H), 4.57 (t, 2H), 4.73 (d, 2H), 180 Mach Ж E 6.72 (dd, 1H), 6.95 (t, 1H), 7.42 (d, 1H), 7.77 (s, 1H), 8.12 -- Ж (d, 1H), 8.89 (s, 1H) , 9.50 (p. 13). SM: (MANI -395.1 ac

M--

IS

(,;

N

Mach Ve / M M I"N NMR (400 MHz, meon-av4) b rprt 2.43 (t, ZN), 3.46 (s,

We are 181 |! 2H), 4.63 (d, 2H), 4.87-4.89 (t, ЗН), 6.71 (dd, 1H), 6.83- - U 7.00 (t, 2H), 7 .61 (d, 1H), 7.80 (c, 1H), 8.57 (d, 1H), 9.49 (c, 1). CM 5: MANI -427.0

H

M--

E E

(F)

N

Mach Ve

M. m E I"H NMR (400 MHz, meon-av4) b rprt 2.46 (d, ЗН), 3.46 (t, 182 |! 2H), 4.64 (t, 2H), 4, 88 (d, 2H), 5.61 (s, 1H), 5.73 (s, 1H), - U 6.72 (d, 1H), 6.86-6.97 (t, 1H), 7 ,48-7.55 (t, 1H), 7.79 (s, her i 1H), 8.51 (d, 1H), 9.49 (s, 1H). I CM5: MANI -409.0

M--

IS

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 o) mech vo; cha M- E b rrt 2.23 (s, ЗН), 3.27 (s, 2H), 4.56 (t, 2H), 4.73 (s, 2H), 183 is 6.73 (dd, 1H), 6.97 (t, 1H), 7.26 (s, 1H), 7.78 (s, 1H), 8.19 s (s, 1H), 8.90 (s, 1H), 9 .50 (c, 1H). GSM5: |IMNI-395.2 ac

M--

IS

(is);

Me in"

Mach Z E b rrt 2.47 (s, ZN), 3.43 (t, 2H), 4.56 (t, 2H), 4.74 (d, 2H), 184 - M 6.73 (dd, 1H), 6.98 (t, 1H), 7.85 (s, 1H), 7.96 (s, 1H), 8.75 (s, 1H), 8.94 (t, 1H), 9, 51 (p. 1). SM: (MANI -445.1 ac

M--

IS

IS

IS

(F)

N

M M

M b ppt 3.45 (d, 2H), 4.56 (t, 2H), 4.77 (s, 2H), 6.72 (dd, 1H), 185 db ME 6.96 (t, 1H ), 8.55 (d, 1H), 8.59 (s, 1H), 8.80 (d, 1H), 8.85 (s,

X y; 1H), 9.15 (s, 1H), 9.54 (s, 1nH). SM: (MANI -431.1

E E

IS

(at)

Me 25 b ppt 1.10 (d, ЗН), 2.07 (s, ЗН), 2.17 (с, ЗН), 3.24 (t, 2Н), 186 M M- 3.87-3 .92 (t, 2H), 3.96-4.00 (t, 1H), 4.55 (t, 2H), 4.69 (s,

Another 2H), 4.91 (d, 1H), 6.72 (k, 1H), 6.96 (t, 1H), 7.47 (s, 1H),

And ska, 8.53 (s, 1H), 9.42 (s, 1H). GSM5: MANI -438.2 noy

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 16)

Mach 25 b rrt 1.10 (d, ZN), 2.08 (s, ZN), 2.17 (s, ZN), 3.45 (t, 2H), 187 Me m i 3.89-3, 93 (t, 2H), 3.96-4.00 (t, 1H), 4.55 (t, 2H), 4.69 (d, this is 2H), 4.91 (d, 1H), 6, 71 (k, 1H), 6.96 (t, 1H), 7.47 (s, 1H),

And 8.53 (t, 1H), 9.43 (s, 1). And CM5: IM--NI-438.2 no 5

M, rya

M is;

Mach y ) | b ppt 1.41 (d, 6H), 2.46 (s, ЗН), 3.40 (t, 2H), 4.54 (t, 2H), 188 M: ME 4.59-4.63 (t, 1H), 4.69 (s, 2H), 6.71 (k, 1H), 6.93 (t, 1H),

M 7.60 (s, 1H), 7.77 (s, 1H), 8.58 (t, 1H), 9.46 (s, 13). I SM5: p, IMANII-408,4

M

M

(is,;

M in

M: sh- E b rrt 2.48 (s, ЗН), 2.53 (s, 1H), 3.41 (t, 2H), 3.75 (t, 2H), 189 M 4.16 (t , 2H), 4.57 (t, 2H), 4.70 (d, 2H), 6.71 (dd, 1H), 6.96

SHE: (t, 1H), 7.63 (s, 1H), 7.79 (s, 1H), 8.57 (s, 1H), 9.46 (s, 1H).

M | And SmM5: IMANI-410,2

In, but (e,;

M in

M: - E b ppt 2.46 (s, ЗН), 3.40 (t, ЗН), 3.75 (t, 2Н), 4.12 (t, 2Н), 190 M 4.55 (t, 2H), 4.70 (d, 2H), 6.72 (dd, 1H), 6.96 (t, 1H), 7.74

SHE (s, 1H), 8.42 (s, 1H), 8.52 (s, 1H), 9.46 (s, 1H). I CM5: / M IMANI-410,2

M,

In, but

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (F)

E E M M b rrt 3.47 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (dd, 1H), 191 | in 6.90-7.21 (t, 2H), 7.78 (s, 1H), 8.95 (s, 1H), 9.12 (s, 1H), and ME 9.42 (s, 1H), 9.50 (c, 1). G CM5: MANI -414 1

In)

M

(9)

М M b ррт 0.84-0.86 (t, 2Н), 0.95-0.97 (t, 2Н), 3.40 (t, 2Н), 192 | g 3.77-3.80 (t, 1H), 4.55 (t, 2H), 4.73 (d, 2H), 6.61 (d, 1H),

ME 6.71 (Kk, 1H), 6.97 (t, 1H), 7.47 (d, 1H), 7.93 (s, 1H), 8.83 (t, x B: ( y; 1H), 9.49 (p, 13). And CM: (MANI -392.2

M-M M-M (F)

H "H-NMR (500 MHz, OM50O-av) b ppt 3.42 (s, 2H), 4.56 (s, 193 E M. M 2H), 4.73 (s, 2H), 5.44 (d, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.55-7.57 (t, 1H), 7.69 (s, 1H), 7.98 ( d, 1H), 8.68 (dd, 1H),

MME 8.79 (s, 1H), 9.48 (s, 1). And SM5: MANI: -395.1

Her 17 xx M-M (F);

Mah Chi). "H-NMR (500 MHz, OM50O-av) 6 ppt 2.18 (s, ЗН), 2.46 (s, 194 M: sh- E ЗН), 3.45 (t, 2Н), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H),

M 6.96 (t, 1H), 7.27 (s, 1H), 7.67 (s, 1H), 8.48 (s, 1H), 8.79 (s, s, 1H), 9, 50 (p. 1). SM: MANI -391.2 ac

M--

Table 2

Pr. IN NMR (400 MHz, OM50-av)

Mo Structure or otherwise shown/data | CM5 (F)

N

Mach E / "H-NMR (500 MHz, OM50O-av) b ppt 2.45 (s, ZN), 3.40 (t, 195 M: - E 2H), 3.84 (s, ZN), 4 .55 (t, 2H), 4.71 (s, 2H), 6.72 (dd, 1H),

M 6.96 (t, 1H), 7.74 (s, 1H), 8.28 (s, 1H), 8.51 (s, 1H), 9.46 (s,

SHE: 1). Sm5: MANI" -380.2 m

M

/ (F)

M

M s / "H-NMR (400 MHz, OM50O-av) 6 ppt 1.44 (t, ЗН), 2.18 (s, 196 в я Е ЗН), 3.44 (t, 2Н), 4, 44 (dd, 2H), 4.57 (t, 2H), 4.72 (s, 2H), Щ- UM 6.72 (dd, 1H), 6.78 (s, 1H), 6.97 ( t, 1H), 7.59 (s, 1H), 8.05

M (c, 1H), 8.68 (c, 1H), 9.46 (c, 1). And SM: (MANI: -421.4 x / to

Gee)

Нн мех во МЕ тняме (500 MHz, ОМ50-ав) 6 ррт 2.27 (с, ЗН), 3.46 (t, 2Н), 197 u 4.56 (t, 2Н), 4.73 ( d, 2H), 6.73 (dd, 1H), 6.98 (t, 1H), 7.12 , (s, 1H), 7.61-7.90 (t, 2H), 8.18 ( s, 1H), 8.77 (t, 1H), 9.48 (s,

She 1H). See: (MANI -443.1 u. M M

E (c) (,;

N

Mach Ve

M. and E "H-NMR (500 MHz, OM50O-av) 6 ppt 2.43 (s, ЗН), 3.48 (t, 198 Х 2Н), 4.56 (t, 2Н), 4.74 (c, 2H), 6.72 (dd, 1H), 6.87-7.09 (t, - U 2H), 7.74 (c, 1H), 7.79 (c, 1H), 8, 66 (c, 1H), 8.88 (c, 1H),

Its price is 9.50 (c, 1H). SM: MANI -427.4

M--

E E

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5

Fo) ml in

Ma ME | H-NMR (500 MHz, OM50O-av) b ppt 2.44 (s, 3H), 3.03 (d, 199 M 6H), 3.45 (t, 2H), 4.56 (t, 2H) . 87 (d, 1H), 8.76 (c, 1H), 9.49 (c, 13). CM: MANI -448.2

X 7

M

AND

(F) (9)

Mach M S b rrt 3.44 (t, 2H), 3.87 (s, ZN), 4.55 (t, 2H), 4.72 (s, 2H), 200 E M.Yu dk E 6, 71 (Kk, 1H), 6.77 (s, 1H), 6.90 (s, 0.25H), 6.95 (t, 1H), 7.01

M (с, 0.5Н), 7.12 (с, 0.25Н), 7.83 (с, 1Н), 9.51 (с, 13). And CM5:

E to IMANI-416,1 )

M

/ (c)

E E M M "H-NMR (500 MHz, OM50O-av) 6 ppt 2.61 (s, ЗН), 3.44 (t, 201 in 2Н), 4.56 (t, 2Н), 4.73 (c, 2H), 6.71-6.99 (t, ZN), 7.55 (d,

ME 1H), 7.59 (s, 1H), 7.89 (d, 1H), 8.80 (s, 1H), 9.48 (s, 1H).

M | in y; And CM5: (MANI -427.2 xx M-M (9)

H IN NMR (400 MHz, COzOb) b ppt 3.27 (t, 2H), 3.43 (d, 202 M. M 2H), 4.51 (t, 2H), 4.71 (s, 2H) , 6.63 (s, 1H), 6.89 (t, 1H), g 8.45-8.52 (t, 2H), 9.01 (s, 1H), 9.97 (s, 1) And CM5: train! y y (Me -363.9 /

Me | M-M

Table 2

Pr. "H NMR (400 MHz, OM5O-v)

Mo Structure or otherwise shown/data | CM5 (o)

M- in IN NMR (400 MHz, SOzOV) b ppt 2.08 (s, ZN), 2.24 (s, 203 M m-K with ZN), 4.58 (t, 2H), 4.63- 4.73 (t, 2H), 6.72 (dd, 1H), 6.91-

TM 7.02 (t, 1H), 7.42 (dd, 1H), 7.62 (dd, 1H), 8.51 (dd, 1H), shshsh- 8.66 (s, 1H), 9, 48 (c, I) I CM: (M-NI:-390.9 m pc o

M n ; / y U M "H-NMR (500 MHz, OM5O-av) 5 ppt 2.25 (s, ЗН), 3.40 (s, 204 Mach ЖЕ 2Н), 4.56 (t, 2Н), 4 .73 (s, 2H), 6.72 (dd, 1H), 6.97 (t, 1H),

W 7.A46-7.48 (t, 2H), 7.72 (s, 1H), 8.46 (dd, 1H), 8.82 (s, 1H), 9.48 (s, 1H). GSM5: MANI -393.1 ac gi x (o)

H IN NMR (500 MHz, OM5O-av) b ppt 3.28 (t, 2H), 4.55 (t, 205 M. and M 2H), 4.78 (s, 2H), 6.72 (dd , 1H), 6.97 (t, 1H), 8.59 (d, 1H), 5 8.66 (s, 1H), 8.71 (t, 1H), 9.07 (s, 1H), 9.56 (c, 1Н), 9.93 (d, Э 18); SM: (MANI -364.1 ish, ish im M-M (o)

Н b ррт 3.29 (with lat., 2Н), 4.54 (t, 9У-8.72 Hz, 2Н), 4.74 (с, 206 Mai 2Н), 6.70 (dd, У-3 .86, 8.63 Hz, 1H), 6.95 (t, 9U-9.44 Hz, 1H), 8.29 (s, 1H), 9.11 (s, 1H), 9.43 (s , 1H), 9.53 (c, 2H). CM: m / 0 E (MNE -363.9 /

M--

B t-

Table 2

Pr. "NMR (400 MHz, OM5O-iv)

Mo Structure or otherwise shown/data | CM5 ate) /

M M IN NMR (400 MHz, methanol-da) b ppt 2.28 (s, 6H), 3.54 (s, 208 g 2H), 5.09 (s, 2H), 7.05 (d, 1H ), 7.41 (dt, 2H), 7.45 (t, ZN),

M 7.78 (d, 1H), 7.91 (d, 2H), 7.95 (s, 1H), 9.40 (s, 1)... S-M: 1 IMaNI-398.9

M-M

AND

/ (F) a

M M g b ppt 2.29 (s, ЗН), 2.46 (t, 4Н), 3.19 (t, 4Н), 5.00 (d, 2Н), 209 M 7.01 (d, 2Н ), 7.16 (dd, 1H), 7.40 (t, 2H), 7.52 (d, 1H), 7.91 and (t, 4H), 8.82 (t, 1H), 9, 47 (c, 1H). GSM8: |MANI-440.2

M-M shk r

N

M M g o

What A b ppt 1.44 (d, ЗН), 1.69 (с, 4Н), 2.44 (k, 2Н), 3.25 (к, ЗН), 210 0 5.04 (d, 2Н) , 7.18 (t, 1H), 7.44 (t, 5H), 8.02 (t, 4H), 8.96

C M-th (t, 1H), 9.50 (s, 1H). SM: |(MANI-439.4 m.y

HO o c -/ 6 ppt 2.23 (s, ZN), 2.41 (d, 4H), 3.54 (t, 4H), 5.02 (d, 2H), 211 a, 6.95 ( d, 1H), 7.40 (t, ЗН), 7.53 (d, 1H), 7.95 (c, 2H), 8.24 а m; (k, 1H), 8.83 (t, 2H), 9.49 (s, 1H). GSM5: NAMES -441.2 / c) o b rprt 2.23 (s, ЗН), 2.43 (s, 4Н), 3.53 (s, 4Н), 5.04 (d, 2Н), sh m. M 7.17 (t, 1H), 7.27 (t, 2H), 7.49 (dd, 1H), 7.53 (d, 1H), 7.74 212) 77 g (s, 1H ), 8.01 (d, 1H), 8.14 (d, 1H), 8.29 (s, 1H), 9415 (t, 1H),

Sm t» 2 9.50 (s, 1H). SM: (MeNI-441,2

M. 2 M-M 779 m Kk b rrt 5.04 (s, 2H), 7.17 (t, 1H), 7.27 (t, 2H), 7.48 (t, 213 B 2H), 8 .02 (d, 1H), 8.15 (s, 1H), 8.49 (t, 2H), 9.08 (s, 1H), ch ik 9.28 (dd, 1H), 9.52 ( c, IN). And SM: (MANI -343.2

She m M

Table 2

Pr. "NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | SM5 m. and in Yav

M --//16 ppt 3.26 (s, ZN), 5.06 (s, 2H), 7.19 (t, 1H), 7.42 (t, 2H), 214 U 7.54 (d , 1H), 8.01 (t, ЗН), 8.25 (s, 1H), 8.45 (d, 2H), 9.54 o Sh (c, 18). GsM5: MANI -420.1 x M-M 8 xx (is) ;/9

N FI

May o ppt 1.18 (d, 6H), 3.45 (t, 1H), 5.06 (s, 2H), 7.18 (d, 1H), 215 | M 7, A1 (t, 2H), 7.54 (d, 1H), 7.91 (d, 2H), 8.02 (d, 1H), 8.26

I; (c, 1H), 8.45 (d, 2H), 9.17 (c, 1H), 9.53 (c, 13). And SM: about M-k (Menr-448,2

From xx tr U /79

Mo b rrt 1.82 (t, 4H), 3.46 (t, 4H), 5.03 (s, 2H), 7.17 (dd, 216 | in 1H), 1.29 (t, 2H ), 7.52 (d, 1H), 7.59 (d, 2H), 8.01 (d, 1H),

M 8.11 (c, 1H), 8.18 (d, 2H), 9.03 (c, 1H), 9.48 (c, 1). SM:

FI in and IMaNr-439,2 (v

N

M. and M b rrt 5.04 (s, 2H), 7.18 (t, 1H), 7.44 (t, ZN), 7.47 (t, 217 | g 6 on), 7.54 ( t, 1n), 8.10 (t, 4H), 9.51 (c, 1). I SM: i 7 (Maeni-34241

M-M

N

M. im b ppt 5.06 (s, 2H), 7.28 (t, 1H), 7.43 (t, 2H), 7.56 (d, 1H), 218 | Shchi 9 8.03 ud, 1n), 8.23 (t, 2H), 8.47 (s, 1H), 8.63 (t, ЗН), 9.53 (s, g»! and 18). SM: (MANI -343.1

M. M-Mm

IS.

Hn IN NMR (400 MHz, methanol-da) b ppt 2.42 (s, 6H), 3.58 (s, 219 Mai o 2H), 5.13 (s, 2H), 7.06-7.18 (t, 2H), 7.40-7.54 (t, ZN), 7.84 sq -/ | (d, 1H), 7.94 (d, 2H), 8.01 (c, 1H), 9.42 (c, 1H). And SM: what; (Man -417.2 r M-M

M n

B b ppt 1.54 (k, 2H), 1.83 (t, 4H), 2.11 (s, ЗН), 2.80 (d, 2H), 220 m -/73.22 (t, 1H ), 5.06 (c, 2H), 7.19 (c, 1H), 7.41 (t, 2H), 7.54 (d, o, and 1H), 7.90 (d, 2H), 8.03 (d, 1H), 8.26 (c, 1H), 8.45 (d, 2H),

Fe: 9.15 (s, 1H), 9.55 (s, 1H). (CM: NAMES -503.2

AM

Table 2

Pr. "H NMR (400 MHz, OM5O-v)

Mo Structure or otherwise shown/data | CM5

IS

N

We M b ppt 9.53 (s, 2H), 9.43 (s, 1H), 9.11 (s, 1H), 8.29 (s, 1H), 221 | that O|b6ovB(t, 1H), 6.70 (dd, 1H), 4.74 (s, 2H), 4.54 (t, 2H), 3.29

Mo U (t, 28). SM: |MeNI" -363.9

She

M--

I t-k

IS.

M M I N NMR (500 MHz, OM50O-dv) b rprt 2.19 (s, ZN), 2.48 (s,

M 6.96 (t, 1H), 7.23 (s, 1H), 7.62 (s, 1H), 8.43 (s, 1H), 8.70 (t, te x y; 1H), 9.46 (c, 1H). (SM: (MANI -391.1. - M-M

M

IS.

NMR NMR (600 MHz, OM5O-dv) b ppt 2.23 (s, 6H) 2.48 (s, (o) ЗН) 2.50 (s, 7H) 3.43-3.47 (t , 2H) 3.50-3.57 (t, 2H) 4.51- 293 bern 4.61 (t, 2H) 4.67-4.78 (t, 2H) 6.69-6.76 (t , 1H) 6.92-7.00

And | M (t, 1H) 7.29-7.47 (t, 1H) 7.61-7.68 (t, 1H) 7.69-7.75 (t,

M | XX 1H) 8.65-8.74 (t, 1H) 9.42-9.51 (t, 1). And SM: xx M-M (MANI -434.2

JSC o

М M b ррт 1.27 (t, ЗН), 2.21 (с, ЗН), 2.76 (k, 2Н), 3.44 (d, 2Н), 224 Z 4.56 (t, 2Н) , 4.72 (s, 2H), 6.72 (dd, 1H), 6.94-7.00 (t, 1H),

ME 7.24 (s, 1H), 7.63 (s, 1H), 8.46 (s, 1H), 8.70 (s, 1H), 9.47 (s, y: i y; 1 ). hom: (MANI -405.2. - M-

Mee M

E. mok "H NMR (500 MHz, OM5O-av) b ppt 0.72-0.85 (t, 4H),

B o 2.46 (s, ZN), 3.44 (t, 2H), 4.45 (Yii, 1H), 4.56 (t, 2H), 4.72 (s, 225 he M 2H), 6.72 (dd, 1H), 6.96 (dd, 1H), 7.69 (s, 1H), 8.51 (s, 1H),

A. t o; 8.77 (c, 1H), 9.47 (c, 1H). SOM: (MANI -434.1

F 2 M-M (in) M

Well

My M NMR (500 MHz, OM5O-ov) b rrt 1.46 (t, ZN), 2.45 (s, 296 | Same as ZM), 3.44 (t, 2H), 4.40 (k, 2H), 4.56 (t, 2H), 4.72 (s, 2H),

Me and 5.72 (dd, 1H), 6.92-7.00 (t, 1H), 7.68 (s, 1H), 8.48 (s, 1H),

AH Tsi and 8.76 (s, 1H), 9.47 (s, 13). And SM: (MANI -422.2 -o M -M

IS

М М "Н NMR (500 MHz, ОМ5О-dv) b ррт 3.29-3.43 (t, 2Н), 297 но в о | 3.91 (s, ЗН), 4.55 (dd, 4Н) , 4.71 (d, 2H), 5.59 (t, 1H), 6.71

M (dd, 1H), 6.95 (t, 1H), 7.76 (s, 1H), 7.81 (s, 1H), 8.58 (t, -m " in 1H)U, 9, 45 (p, 1). SM: (MANI -396.1

M- M-M

Table 2

Pr. "H NMR (400 MHz, OM5O-av)

Mo Structure or otherwise shown/data | CM5

E m. M with b rrt 2.24 (s, ЗН), 4.56 (t, 2H), 4.73 (s, 2H), 6.73 (dd, 1H), 2280 si | M 6.92-7.01 (t, 1H), 7.58 (s, 1H), 7.79 (s, 1H), 8.48 (s, 1H),

GO 7 9.50 (c, 1H). And SM: MANI -410.8

M. 2 M-M o

Н "Н NMR (500 MHz, ОМ5О-dv) b ррт 1.26 (t, ZN). 2.47 (s, 229 M. NMR ZN), 2.77 (k, 2Н), 3.44 (s , 2H), 4.56 (t, 2H), 4.72 (s, 2H), g 6.72 (dd, 1H), 6.97 (t, 1H), 7.18 (d, 1H), 7.68-7.58 (t, 2H),

ME 18.70 (c, 1H), 9.47 (c, 1H). GSM8: (MANI: -405.4

She is 7

M-

M m

IS

H ma and M "H NMR (500 MHz, OM50O-dv) b rprt 2.04 (s, HN), 3.41 (s, 280 ei RH), 3.93 (s, HN), 4.55 ( t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), rock M 6.99-6.92 (t, 1H), 7.02 (d, 1H), 7.65 (c, 1H), 8.05 (d, 1H), c r in B, 8.78 (c, 1H), 9.45 (c, 13). I CM: MANI -407.1

IS

M M I N NMR (500 MHz, OM5O-dv) b ppt 3.41 (s, 2H), 4.55 (t,

Ex 2H), 4.76 (s, 2H), 6.72 (dd, 1H), 7.00-6.93 (t, 1H), 7.45-21 t o

M 7.41 (t, 1H), 7.92 (19, 1H), 8.65 (d, 1H), 8.68 (s, 1H), 8.81 and: 7; (d, 1H), 8.90 (c, 1H), 9.53 (c, 1H). SM: MANI -363.1

YAM M-M

IS

М М b ррт 2.48 (с, ЗН), 3.42 (d, 2Н), 4.56 (t, 2Н), 4.74 (с, 2Н), 292 шей О 6.71 (dd, 1Н ), 6.96 (dd, 1H), 8.15 (s, 1H), 8.42-8.40 (t, 2H),

M 8.80 (s, 1H), 9.09 (d, 1H), 9.46 (s, 1H). And SM: and: I; (Man -376.9

M-

M M

IS

M M I N NMR (500 MHz, OM5O-dv) b ppt 2.19 (s, ZN), 3.41 (t, 253 g o |2H), 4.55 (t, 2H), 4.70 (c, 2H), 6.71 (dd, 1H), 6.93-6.98 (t,

M 1H), 7.53 (s, 1H), 7.99 (s, 1H), 8.25 (d, 1H), 8.78 (s, 1H), -y XX 9.52 (s, 1H ). SM: MANI: -366.1 me M-m

E. m. VN b ppt 3.25-3.44 (t, 2H), 4.55 (t, 2H), 4.62 (d, 2H), 4.74 (s, -h M 8.15 (s, 1H), 8.51 (dd, 1H), 8.81 (s, 1H), 9.19 (dd, 1H), 9.51 no. L sc (s, 1). CM: MANI - 392.9

M

Table 2

Pr. IN NMR (400 MHz, OM50O-av)

Mo Structure or otherwise shown/data | CM5

IS

N

M.O OM IN NMR (400 MHz, methanol-da) b ppt 3.48 (d, 2H), 4.59 (t, 235 | g (e; 2H), 4.75 (d, 2H), 6 .66 (dd, 1H), 6.80-6.93 (t, 1H), 7.71 (d,

E and 1H), 9.43 (d, 1H). CM: MANI" -303.9 you,

M-M

IS.

M M IN NMR (500 MHz, OM50-av) b rrt 2.10 (s, ZN), 2.16 (s, 296 | M o | ZN), 3.41 (s, 2H), 4.56 ( t, 2H), 4.70 (s, 2H), 6.72 (dd, 1H),

M 6.92 (s, 1H), 6.94-6.99 (t, 1H), 7.78 (s, 1H), 8.88 (s, 1H), -y X y; 9.50 (c, 1H). SM: MANI -379.9 mu M-M

IS.

M M IN NMR (500 MHz, OM50-av) b rrt 3.40 (d, 2H), 4.55 (t, 297 vi o 2H), 4.71 (s, 2H), 6.56-6, 60 (t, 1H), 6.71 (dd, 1H), 6.92-

M 6.99 (t, 1H), 7.78 (d, 1H), 8.18 (s, 1H), 8.79 (d, 1H), 9.54 st y y; (p. 183. SM: (MANI -352.1 --M М-М

IS.

M M IN NMR (500 MHz, OM50-dv) b rrt 2.49 (s, ZN), 3.41 (d, 238 | M (o) 2H), 4.55 (t, 2H), 4.72 (c, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), street M 8.14 (c, 1H), 8.91 (c, 1H), 9.22 (c, 1H), 9.56 (s, 1H). I. CM5:

M and | in; IMANIG-367,1 in" М-М

IS.

M n IN NMR (500 MHz, OM50-dv) b rrt 2.14 (s, ZN), 3.40 (d, 299 vii o 12), 4.54 (t, 2H), 4.70 (s, 2H), 6.71 (dd, 1H), 6.93-6.99 (t,

M 1H), 7.59 (s, 1H), 8.13 (s, 1H), 8.59 (s, 1H), 8.70 (s, 1H), - i y; 9.54 (c, 1H). SM: MANI -366.1 2-- M M-M

IS

M M IN NMR (500 MHz, OM50-av) b rrt 3.41 (d, 2H), 4.54 (d, 240 | with o! 2H), 4.71 (s, 2H), 6.72 ( c, 1H), 6.96 (c, 1H), 7.14 (c, 1H),

M 7.83 (s, 1H), 8.05 (s, 1H), 8.46 (s, 1H), 8.83 (s, 1H), 9.53 (s,

TM 18). SMm5: (MANI -352.1 - and kh

M- M-M

IS.

M M IN NMR (500 MHz, OM50-dv) b rrt 3.42 (t, 2H), 4.55 (t, odi v e) 2H), 4.73 (d, 2H), 6.72 (dd , 1H), 6.97 (t, 1H), 8.19 (s, 1H),

M 8.41 (s, 1H), 8.97 (s, 1H), 9.44 (s, 1H), 9.57 (s, 1). I. CM5: ac 7; (IMANE-353.1 kh-m М-М

IS

H NMR NMR (400 MHz, methanol-aa) b ppt 2.48 (s, HN), 4.49-

M M 4.40 (t, 1H), 4.61-4.52 (t, 2H), 5.07 (d, 2H), 5.72 (d, 1H), 242 | in o 6.81 (dd, 1H), 7.12-6.98 (t, 1H), 7.44-7.46 (t, 1H), 7.66 (s, hu and no 1H), 7 .83 (d, 1H), 8.51 (d, 1H), 9.44 (c, 13). And SM5: to her (Men -392.9 - M-M

M

Table 2

Pr. IN NMR (400 MHz, OM50-av)

IS.

M M I N NMR (400 MHz, methanol-da) b rrit 4.46 (dd, 1H) 4.59 g (c) (dd, 1H) 4.65 (s, 2H) 4.86 (Brg 5 ., 1H) 5.07 (d, 2H) 5.72 (d, 243 s M 1H) 6.81 (dd, 1H) 7.06 (t, 1H) 7.49 (dd, 1H) 7.75 (c, 1H) in y; but 7.89-7.96 (t, 1H) 8.64 (d, 1H) 9.44 (c, 1H). And CM5:

M M-M IMANI-408.8 on

IS

M M IN NMR (400 MHz, methanol-da) b ppt 2.41-2.50 (t, ЗН) with О 0 |4,Ab (dd, 1Н) 4.59 (dd, 1Н) 4.87 ( bg 5., 1H) 5.08 (d, 1H) 244 s M 5.68-5.76 (t, 1H) 6.81 (dd, 1H) 7.06 (t, 1H) 7.50 (t , 1H) in y, but 7.64 (d, 1H) 7.75 (s, 1H) 8.46 (d, 1H) 9.44 (s, 1H). I SM:

M M-M IMANI-408.8 o

IS

M M "H NMR (500 MHz, OM50O-av) 6 ppt 2.25 (s, ЗН), 3.41 (t, 245 | | in е) 2Н), 3.43 (s, ЗН), 4, 45 (t, 2H), 4.70 (s, 2H), 6.53 (dd, 1H),

M M b.78-6.66 (t, 1H), 6.83 (s, 1H), 7.52 (s, 1H), 9.11 (s, 1H). - and i y; SM: MANI -379.9

M M--M

E. PHARMACOLOGY AND APPLICATION

As a key component of the PKS2 complex, EEO has no intrinsic enzymatic activity. However, it is critically important for the proper functioning of RKS2. EEO binds directly to NZK27tez, and this binding event localizes the PKS2 complex to the chromatin substrate and allosterically activates methyltransferase activity. Targeting the allosteric site in the regulatory subunit of EEJU RKS2 may offer a new and unique angle for preferential or additional relatively direct targeting of the competition mechanism of ZAM E2H2 or RKS2. Therefore, targeting EEU represents a very attractive strategy for the development of new therapies for the treatment of many forms of cancer. In particular, there is a need for small molecules that inhibit the activity of PKC2 by targeting the EEJ. It has been found that the triazolopyrimidine derivatives disclosed in this invention are suitable for targeting EEO for the treatment of EEO or PEC2-mediated diseases or disorders, especially cancers.

The suitability of the compounds of the present invention can be demonstrated using any of the following test procedures. Compounds of the present disclosure were evaluated for their ability to inhibit PKS2 activity in a pentameric complex

E2H2g, 50212, EE, KBrar48 and AEVR in biochemical tests. The ability of the compounds of this disclosure to inhibit the cellular activity of PKS2 was evaluated by analyzing histone 3 lysine 27 methylation in human cell lines. The ability of the compounds of this disclosure to inhibit cancer was derived from their ability to modulate activity in human cancer cell lines that have a specific dependence on PKS2 activity to support malignant growth.

Test for competitive binding of the peptide EEO-NZK27Mez AiIrpazsgeep (a-5step)

To evaluate the potential of the compounds in the test of competitive binding of EEO-NZK27MeZz, the compounds were serially diluted 3-fold in OM5O to obtain a total of twelve concentrations.

Then, the compounds at each concentration (75 nl each) were transferred with the help of Mozdiyo to 384-well plates Regkip EIteg RgohiRiate 384 rii5. 8 μl of solutions containing 30 nM EEO protein (1-441)-Hi5 and 15 nM peptide biotin-NZK27Mez (19-33) in buffer (25 mM HERE5, pH 8, 0.02 95

Tmeep-20, 0.5 95 VB5A) was added to the wells and then incubated with the compound for 20 minutes.

zo A mixture of AIrpabsgeep beads for detection was prepared immediately before use by mixing nickel chelate acceptor beads and streptavidin donor beads in a ratio of 1:1 (Regkip EITeg, Rhodisi Mo. 6760619C/M/K) in the buffer described above. Then 4 μl of the detection bead mixture was added to the plate and incubated in the dark at room temperature for 1 h. The final concentration of donor and acceptor beads was 10 μg/ml for each. Plates were read on an Epmisiop (RegkipEIteg) using AIIrpazsgeep settings adapted to optimal signal detection with a 615 nm filter after sample excitation at 680 nm. The emission signal at 615 nm was used to determine the amount of compound inhibition. AIrpazsgeep signals were normalized based on the reading obtained from the positive (maximum signal control) and negative control (minimum signal control) to obtain the percentage of activity remaining. The data were then used to construct a dose-response equation using the Neiiiob5 program (Momagiz) to obtain ISvo values. Neio5 is its own software

Momagiv for the analysis of test data using the methods described by Mohitoi, O. R., et al.

Meadisipe, 12:2025-2042 (1993); Rottepko, I. ei ai, Sotrshiieg Meinodz apa Rgodgatz ip Vioteaisipe, 82, 31-37 (2006); Zeratsydny, 9. Y., RNnaptaseciisa! Journal of Science, 10:128-134 (2011); KePu, b. hey ay.,

Vioteiisv, 46(4):1071-1085 (1990); and Capt, M. ei ai., Uoigpai oi eiaiiviisa! Zoimage, 33(7): (2010) (author: Ritsip Viiodisa! Sto Siguez m/yy V, radev 1-21, available at pEr:/Lumly. |viaivoy.ogd/).

Each compound was reverse-screened to determine if it interacted with the AIrpazsgeep beads. Compounds were diluted as described in the previous section, and the assay was performed by adding 12 μL of 10 nM biotin-miniPE G-Nieb peptide in the buffer described above and incubating for 20 minutes at room temperature before adding beads of 10 μg/mL of each compound. The tablets were then incubated for 1 hour. at room temperature in the dark, then read on Epmisop.

Test Y C-M5 EE

Representative compounds of this disclosure were serially and separately diluted 3-fold in OM5BO to obtain a total of eight or twelve concentrations. Then the test compounds in each concentration (120 nl of each) were transferred using Mozdiyo u

384-well plates RegkKip EIteg RgohiRiase 384 rii5. Solutions (b μl) of 24 nM wild-type PKS2 complex (UKHRES2) and 2 μM ZAM in reaction buffer (20 mM Tti5, pH 8.0, 0.1 95 B5A, 0.01 95

Thiop, 0.5 mM OTT) was added to the wells, then incubated with the test compound for 20 minutes. Solution b μl C μM peptide substrate НЗ3ЗК27Meoby (histone НЗ (21-44| - biotin) in

Reaction buffer was added to initiate each reaction. The final components in the reaction solution include 12 nM ULRKS2 complex, 1 µM ZAM and 1.5 µM NZK27teo peptide with variable concentration of compounds. The positive control consisted of enzyme, 1 μM 5AM, and 1.5

MCM of the substrate in the absence of the test compound, and the negative control consisted of only 1

MKM ZAM and 1.5 µM substrate. Each reaction was incubated at room temperature for 120 minutes, then stopped by adding 3 μl of inhibitor solution (2.5 95 TEA with 320 nm a4-

ZAN). The reaction mixture was centrifuged (centrifuge Errepaogi 5810, Rotor A-4-62) for 2 minutes at 2000 rpm. and read on a triple quadrupole mass spectrophotometer

АРИ 4000 from Tigrshop 5rgau (Arriyea Viozuuyut), mated with Rgotipepse ORI S (ZPPitaa?y). BAS production levels were then normalized based on values obtained from positive and negative controls to obtain percent enzyme activity. The data were then used for a dose-response equation using the Neio5 program to obtain IC values of the test compound.

EGISA test (NZK27 methylation)

Representative compounds of this disclosure were serially and separately diluted 3-fold in OM5BO to obtain a total of eight or twelve concentrations. Compounds were then added to 5401 cells cultured in a 384-well plate at a dilution of 1:500 to obtain a peak concentration of 20 µM. The cells were then cultured for 48 h. before the EGISA procedure.

Histone extraction: Cells, in a plate with 384 wells, were washed with RV5 (10 x buffer RV5 (80 g of mass (Zidta, 53014), 2 g of KSI (Zidta, 60128), 14.4 g of MagHRO" (Zidta, 55136), 2 ,4 g of KNgRO" (5idta,

PO791) per 1 l of water, pH 7.4) and lysed by adding lysis buffer (0.4 n. NS; 45 μl per well).

The tablet was gently shaken at 4 C for 30 minutes. The cell lysate was neutralized with a neutralizing buffer (0.5 M dibasic sodium phosphate, pH 12.5, 1 mm OT; 36 μl per well). The plate was shaken to ensure that the lysates were well mixed into the protocol

EPZA.

EGIZA protocol: cell lysates were transferred to the wells of a 384-well plate, and the final volume was adjusted to 50 μl per well using PB5. The tablet was isolated, centrifuged at 2000 rpm. for 2 minutes and incubated at 42C for about 16 hours.

The tablet was washed with TV5T buffer (1 x TV5 (10x TV: 24.2 g of Tiz (bBidta, T6066), 80 g of Masi 60 (Bidta, 53014) per 1 l of water and pH 7.6, proven using NS) with 0, 1 95 Hmeep-20).

Blocking buffer (TV5T, 595 VA; 50 μl per well) was added, and the plate was incubated for 1 h. at room temperature. Blocking buffer was removed and primary antibody (30 μl per well) was added. The following dilutions were performed using blocking buffer: for the anti-NH3K27teZ antibody (Se! Zidpainpo Tesppoiodu, 29733) the dilution was 1:1000; for the anti-NZ3K27teg antibody (Sei! Zidpaip9u Thesppoiodu, 29288) the dilution was 1:100; for the anti-NZ antibody (Absat, Sai24834), the dilution was 1:1000.

The primary antibody was incubated in the plate at room temperature for 1 hour. The wells were washed with TV5T and incubated with the secondary antibody for 1 hour. at room temperature. For secondary antibodies, the following dilutions were performed using blocking buffer: anti-rabbit antibody (Chaskbop IttypoKezeagsy, 9111-035-003) dilution was 1:2000; and for the anti-mouse antibody (Seyi Bidpaipu Thesppoiodu, 7076) the dilution was 1:1000. After 1 hour after incubation at room temperature, the wells were washed

TV5T. ESI substrate (Riegse, 234080) was added in an amount of 30 μl per well, and the plates were centrifuged at 2000 rpm. within 2 minutes. The signal was read using

RegkipEIteg Epmysiop Keadeg. NZK27 methylation readings were normalized using the NZ signal, and then percent inhibition was calculated against OM5O-treated samples. The data were then used to construct a dose-effect curve using the NEO5 program to obtain the IC values of the test compound.

Western blot analysis

Representative compounds of the present disclosure were analyzed for their ability to selectively inhibit PKC2. Western blotting was performed using standard methods of molecular biology. Cells were lysed in lysis buffer 505 (MiiShiroge,

Satshego-163), and the protein concentration was measured by the BSA protein test (Riegsie, Sai RI 23221).

Antibodies for Western blotting: anti-E2H2 (23147), anti-NZ (29715), anti-NZ3Kite1 (59723), anti-NZ3Cateag (59725), anti-NZ3Kai4tez (29727), anti-NZ3KUteag (29753), anti- NZKZbteg (29758), anti-NZK27te2 (29755) and anti-NZK27tez (29756) were purchased from Seiyi Bidpaipud Tespoyodu (Denvers, MA, USA). Anti-NZKOte1! (207-395), anti-NZ3K2g7thei (207-448) and anti-

NZKZbtei (207-548) were purchased from Michigan (Billerica, Massachusetts, USA). Anti-NZ3ZKZbtez (ar9050-100) was purchased from Arsat (Cambridge, UK). Anti-NZ3KOtez (Zh39161) was

Zo was purchased from Asiime Moi (Carlobad, CA, USA).

The compounds of this disclosure specifically inhibit methylation of the PES2 substrate

NZK27. This can be demonstrated by their ability to inhibit NSK27te2 and NSK27tase in many human cancer cell lines, examples include rod-like cells (5401) and lymphoma cells (M/UZO-0I C12, KAVRAB422, 50-ONI 4). Selectivity is profiled against many other methylation assays, for example: НЗК4Ате2; НЗКОТе2; NZ3KZbtez; and NZK7O theses.

Analysis of cell proliferation

Cells of B-cell lymphoma KAKRABZ422 were cultured using standard cell culture conditions in KRMI-1640 (Ipmigodep, sai 211875), supplemented with 15 95-m EV5 (Ipmigodep, sai

Zh10099-141) in a humidified incubator at 3720, 5 95 СО". To assess the effect of RES2 inhibition on cell proliferation, exponentially growing cells were seeded at a density of 1 x 1095 cells/ml in a 12-well plate (Soptipod, sai ZHI 53513). After seeding the cells, the compound according to this disclosure was added to the cell medium (in concentrations from 0 to 100 µM, a series of 3x dilutions). The number of viable cells was determined every 3-4 days for a maximum of 14 days using Mi-SEGI. (Vesktap Soshceg). On the days of cell counting, new growth media and compound were added, and cells were split again to a density of 1x105 cells/ml. The total number of cells was expressed as separated viable cells per ml. Dose-effect curves and values

ISvo were generated using Rgizt.

Analysis of pharmacokinetic properties

The pharmacokinetic properties of the compounds disclosed in this invention can be determined using the protocol described below.

A representative compound according to this disclosure was dissolved in 10 95 RESZO0, 10 95 Bo! shoi

H5 15 and 80 95 acetate buffer pH 4.65 to obtain a final concentration of 0.2 mg/ml for intravenous (IM) and oral (PO) administration.

For the PK study in rats, a total of three male Zrgadce Juauleu rats were used for IM and RO PK studies in rats, respectively. The compound solution was administered as a single IM bolus at 1 mg/kg and as a single oral (PO) at 2 mg/kg, respectively. Blood samples (approximately 150 μl) were collected via jugular cannula at appropriate time points.

For the PK study in mice, a total of twelve male ISC mice were used for MI and RO studies, respectively. The composition solution was administered by a single IM bolus in the amount of 1 mg/kg and a single oral administration (PO) in the amount of 2 mg/kg,

in accordance. Blood samples (approximately 150 μl) were collected via retroorbital puncture (150 μl/mouse), after isoflurane anesthesia, or via cardiac puncture (terminal collection) at appropriate time points (p-3).

Samples were collected in tubes containing KZ-EOTA and stored on ice until centrifugation.

Blood samples were centrifuged at approximately 8,000 rpm. for two minutes at 2-8 °C, and the resulting plasma was separated and stored frozen at approximately -80 °C. After addition of the internal standard, plasma samples were quantified using GsC-

M5/M5 using a calibrated curve. PK parameters, including the area under the concentration curve (AOC), mean residence time (MET), plasma clearance (CI), volume of dynamic equilibrium of distribution (maz5), half-life (1/2), maximum concentration (Cmax), time of maximum concentration (Tmax) and oral bioavailability (BE 9b) were calculated using the following equations:

PBX to ! са 0 0 І0СЯ arms doc

Y is time, and C is the plasma concentration at that time (0; rozem is the intravenous dose; and Uozeogi is the oral dose.

SI-Oozem AOS y2-0.693 x MAT

UAZV-SI" MAT

E Uo- (ovem x AOSoga)/0o56oga x AOS) x 100 to

High-throughput equilibrium solubility test protocol

The compounds of this disclosure were first dissolved in an amount of 10 mM in pure OM5O. 20 μl of each stock solution in OM5BO was transferred into 6 wells on a 96-well plate.

The OM5O solvent was dried with a Sepemas evaporator at 302C, 1 mbar vacuum for 1 hour.

After adding 200 μl of buffer solutions (pH 6.8, or Razvie), the tablet was isolated and shaken at 160 rpm. within 24 hours at room temperature. The tablet was centrifuged at 3750 rpm. for 20 minutes, 5 μl of the supernatant was mixed with 495 μl of MeOnH/NgO (1:1). Stock solutions of 0.01 μm, 0.1 μm, 1 μm, 10 μm were obtained in several stages of dilution for calibration curves. The supernatant was quantified by HPLC or

From IIS/M5 using a calibration curve. Equilibrium solubility was determined with high throughput based on the concentration of the supernatant.

Efficacy studies in a mouse xenograft model

All the conducted experiments were carried out on athymic female Myde-pi mice at the AAAGAS certified stand. Animals were housed under 5PE conditions in individual ventilated cages at constant temperature and humidity (i.e., 20-26 "С; 40-70 95) in the number of 5 or fewer animals per cage. The animals had free access to sterilized irradiated dry pellet feed and sterile drinking water All procedures and protocols were tested

Ipziyshopai Apitai Sage apa O5e and internal commission.

Human B-cell lymphoma Cagraz 422 cells were cultured in KRMI-1640 medium (Sirso; 11875-093) supplemented with 15 95 EV5 (C1ibso; 10099-141) and 1 95 Rep 5iger (Sibso; 15140-122) at 372Sb in an atmosphere of 595 SO: in the air. Cells were kept in suspension in culture at concentrations from 0.5 to 2x105 cells/ml. Cells were split 1:3 every 2-4 days.

To establish a tumor xenograft model, cells were collected, suspended in RV5, mixed with Maihide! (VO Viozsiepse) in a volume ratio of 1:11 at a concentration of 1x109 cells/ml and then injected subcutaneously into the right side of nude mice bBaiB/s (Mpa! Kimeg) at a concentration

Bh105 cells per animal.

The compound was formulated as a suspension in 0.5 96 methyldelulose (MC) and 0.5 95 Tmeep 80 in mM rnb,8 buffer (obtained on site according to OBR) and administered by oral feeding in specific doses. 50 Treatment was initiated when the average tumor volume reached 100-300 mm3. Tumor growth and body weight were monitored at regular intervals. The two largest diameters, width (M/) and length (), of xenograft tumors were measured manually with a caliper, and tumor volume was estimated using the formula: 0.5 x G. x UM2.

When applicable, results were presented as mean - S.E.M. Graphics and statistical analysis were performed using SgarpRaid Rgizt 5.00 (sgarpRaid 5oiimage).

Data on changes in tumor and body weight were analyzed statistically. If the differences in the data were normally distributed (Bartlett's test for level of difference), the data were analyzed using a one-tailed AMOMA with Dunnett's rosy-tailed test to compare treatment versus control. Rosie Tikeu's post test was used for intragroup comparison. In another case, the test constructed according to KgizKa!-UMaiYiiye was used

Ex.

As a measure of efficiency, the value of 95T1/С was calculated at the end of the experiment according to: (Volume of treated tumor/volume of tumor and control) 5100

Regression of the tumor was calculated according to: (The volume of the tumor produced by the volume of the tumor produced at the beginning); 5100 where DL tumor volume represents the average tumor volume on the day of assessment minus the average tumor volume at the beginning of the experiment.

The examples disclosed below were tested in the EEO binding assay of AiIrpazsgeeeep, I C-M5 and/or EHIZA described above and were determined to have EEO inhibitory activity.

A range of ISvos values of 5 μM (5000 nm) was observed.

Table 3, below, lists the values of IC 20 in EEO (a) the AIrpabsteep binding test, (b) the IC-M5 test, and/or (c) the EGISA test measured for the following examples. "M/A" means "not assessed".

Table C (a) (B) (c) 8-(1,3-dimethyl-1H-pyrazol-5-yl)-M-(5-fluoro-2,3-1 dihydrobenzofuran-4-ylylmethyl)-I (1,2,4|griazoli|4,3- 0.0041 0.0082 0.0009 s|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-2 methylpyridin-3-yl)-I1,2,4|triazolo|4,3-c|Ipyrimidin- 5- 0.0059 0.0089 0.0026 amine 8-(2,4-dimethylpyrimidin-5-yl)-M-(5-fluoro-2,3-

From dihydrobenzofuran-4-ylmethyl)-I(1,2,4|griazolo|4,3- 0.0038 0.0064 0.0034 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-4|Isopropyl-3-methyl-1H-pyrazol-4-yl)-P1,2,4| griazolo|4,3- 0,0032 0,0039 0,0021 s|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-5 | methoxy-4-methylpyridin-3-yl)-(1,2,4|triazolo|4, 3- 0.0048 0.0097 0.0029 c|pyrimidin-5-amine 8-(6-cyclopropyl-2-methylpyridin-3-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-ylylmethyl) )-I(1,2,4|griazoly|4,3- 0.0052 0.0077 0.0038 cIpyrimidin-5-amine (3-(5-((5-fluoro-2,3-dihydrobenzofuran-4- 7 subject, 2,4|griazolo|4,3-c|Ipyrimidin-8-yl)upyridin-2-yl)umethanol 8-(2-cyclopropyl-4-methylpyrimidin-5-yl)-M-(5-fluoro -2,3- dihydrobenzofuran-4-ylylmethyl)-I(1,2,4|griazolo|4,3- 0.0049 0.0072 0.0029 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-isopropoxy-4-methylpyrimidin-5-yl)-(1,2,4|griazolo|4,3- | 0.0041 0.0079 0.0035 c|pyrimidin-5-amine -(5-((5-fluoro-2,3Z-dihydrobenzofuran-4-10 (l)methyl)amino)-(1,2,4 |triazoles|4,3-s|pyrimidine-8- 0.0073 0.0138 0.001 yl)pyridine 1-oxide

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-11 (dimethylamino)methyl)phenyl)-I|1,2,4|triazolo|4,3- 0.0069 0, 02 0.0144 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-12Kmethylsulfonyl)phenyl)-I|1,2,4|griazolo!|4,3- 0.0079 0.0159 0 ,0176 c|pyrimidine-5-amine

Table C (a) (b) (c)

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-oz Metic 2,4|griazoloi4,3-s|Ipyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-(1- 14 Kpyrrolidin-1-yl)ethyl)phenyl)-(1,2,4|griazolo|4,3- 0.0078 0.0128 0.0274 c|pyrimidin-5-amine 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 15. |1,2,4)triazolo| 4,3-s|Ipyrimidin-8-yl)-M, M- 0.0128 0.0206 0.0198 dimethylbenzenesulfonamide

Methyl-M-(2,3-dihydrobenzofuran-4-yl)-8-pyridin-3-yl)-

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(pyridin-4-yl)-

Methyl-N-(2,3-dihydrobenzofuran-4-yl))-8-(2-(4-18 methylpiperazin-1-yl)pyridin-4-yl)-1,2,4Htriazolo!|4,3- 0.0185 0.0279 | MA c| pyrimidine-5-amine

M-(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 19. |(1,2,4)triazolo|4,3-c|Ipyrimidin-8-0, 0189 0.0192 0.0401 yl)/uphenyl)umethanesulfonamide

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-(4- | methylpiperazin-1-yl)pyridin-3-yl)-I1,2,4Itriazol!|4,3- 0.0144 0.0171 0.0783 c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-21 methoxypyridin-3-yl)-(1,2,4)griazolo|4,3-c|Ipyrimidin-5-0 .0252 0.026 0.1503 amine 8-(4--(dimethylamino)methyl)phenyl)-M-(2-methyl-2,3- 22 |dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4 ,3- 1,59822 1,80195 |MA c|pyrimidin-5-amine 8-(4--(dimethylamino)methyl)phenyl)-M-(5-fluoro-2,3- 23 |dihydrobenzofuran-4-yl )methyl)-I(1,2,4Itriazoloi4,3- 0.0311 0.0257 0.0424 c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1,3,5-24 rimethyl-1H-pyrazol-4-yl)-(1,2,4|griazolo!|4, 3- 0.0304 0.037 0.162 c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1-methyl-1 H-

ED 2,4|griazoly|4,3-s|Ipyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(2-fluoro-4- 26 (methylsulfonyl)phenyl)-I|1,2,4|htriazoloi|4,3- 0.0099 0.0171 0.0448 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(3-27 methylsulfonyl)phenyl)-I|1,2,4|htriazoloi|4,3- 0.0199 0.0472 0, 4655 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-28 (methylsulfonyl)pyridin-3-yl)-(1,2,4|triazolo|4,3- 0.0111 0 .0276 0.4153 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-(piperidin-29-ylsulfonyl)phenyl)-(1,2,4|griazolo|4,3-s|Ipyrimidine-5 - | 0.0081 0.0145 0.214 amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1,3-dimethyl- z H-pyrazol-4-yl)-(1,2,4griazolo|4,3-c|pyrimidine -5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(2-

ED 2,4|griazolo|4,3-c|Ipyrimidin-5-amine 8-M-(2-chlorophenyl)(2,3-dihydrobenzofuran-4-yl)methyl)-

Table C (a) (b) (c)

M-(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 33 |(1,2,4)triazolo|4,3-c|Ipyrimidin-8-yl)- 2- 0.0285 0.0175 0.2974 fluorophenyl)methanesulfonamide -(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 34 (1,2,4)griazolo|4 ,3-s|pyrimidin-8-yl)-1H-pyrazol-1- 0.0375 0.0494 1.9507 yl)ethanol

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-(2- (dimethylamino)ethyl)phenyl)-(1,2,4)|Igriazolo|4,3- 0.0083 0.0153 0.0334 c|pyrimidine-5-amine

Methyl-N-(2,3-dihydrobenzofuran-4-yl))-8-(5-methyl-6-(4-36|methylpiperazin-1-yl)pyridin-3-yl)-1,2,4Itriazol! |4,3- 0,0185 0,0224 0,0683 s|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-37 (methylsulfonyl)phenyl)-I|1,2,4|htriazoloi|4,3- 0.0123 0.0207 0.0134 c|pyrimidin-5-amine -(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)-

ET; 2,4|griazoly|4,3-s|Ipyrimidine-8-ylphenoxy)ethanol

M-(2-fluoro-4-(5-((5-fluoro-2,3-dihydrobenzo-furan-4-39(|l)methyl)amino)-(1,2,4|triazolo|4,3 -c|pyrimidine-8- 0.0178 0.0175 0.0227 yl)/uphenyl)umethanesulfonamide 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- |1,2, 4|)triazolo|4,3-c|Ipyrimidin-8-yl)-M- 0.0562 0.0566 1.4368 benzenesulfonamide (2-hydroxyethyl) (4-(5-((2,3-dihydrobenzofuran-4 -yl)methyl)-amino)- 41. (1,2,4)triazolo|4,3-c|Ipyrimidin-8-yl)/phenyl)(piperazin-1-| 0.0132 0.0097 0.4748 yl)umethanone 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 42. ||1,2,4)triazolo|4,3-c|Ipyrimidin-8-yl) -M, M- 0.0525 0.0861 02203 dimethylbenzamide -(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 43 (|(1,2,4)triazolo|4,3 -c|Ipyrimidin-8-yl)-M, M- 0.0309 0.0331 0.2471 dimethylbenzamide

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-yl methyl 1,2,4)triazolo|4,3-c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8- 450 Methy M te 2,A|griazolo|4,3-c|Ipyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-(1-46(Cpyrrolidin-1-yl)ethyl)phenyl)-(1,2,4|griazolo |4,3- 0,0435 0,064 0,0048 s|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4- diethyl, 2,A|griazolo!|4,3-c|pyrimidin-5-amine 8- (b-aminopyridin-3-yl)-M-(2,3-dihydrobenzofuran-4-4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 49 (|( 1,2,4)triazolo|4,3-c|Ipyrimidin-8-yl)-M, M,2- 0.0125 0.0128 0.4662 rimethylbenzamide 8-(4-chloropyridin-3-yl)-M -(2,3-dihydrobenzo-furan-4-ovo bolorti 2,4 griazoloi|4,3-s|Ipyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(pyrimidin-5-

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-52|methylpyridin-3-yl)-(1,2,4)triazolo|4,3-c|pyrimidin-5- 0.0709 0.047 0.1061 amine

Table C (a) (b) (c)

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-(2-53 (dimethylamino)ethyl)pyridin-3-yl)-(1,2,4|Itriazoloi|4,3 - 0.0124 0.0287 0.141 c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(2-54|methoxypyrimidin-5-yl)-(1,2,4Hygriazoloi|4,3-s|Ipyrimidin- | 0.0291 0.0546 0.1439 b-amine (l)methyl)amino)-11,2,4|griazolo|4,3-c|Ipyrimidin-8-yl)-M, 0.0211 0.0318 0.0131

M-dimethylbenzamide

Methyl-N-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-56 (methylsulfonyl)pyridin-3-yl)-P1,2,4|griazolo!|4,3- 0.0196 0.0309 0.0493 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-57|methylpyridin-3-yl)-(1,2,4)triazolo|4,3-s| pyrimidine-5- 0.0084 0.0186 0.0334 amine 8-(6-amino-4-fluoropyridin-3-yl)-M-(2,3-58 dihydrobenzofuran-4-yl)methyl)-/1, 2,4)triazoloi|4,3- 0,0063 0,013 0,1241 c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(3,5-59|dimethylisoxazol-4-yl)-1,2,4|Hygriazolo|4,3-s|Ipyrimidine- | 0.0318 0.0387 0.086 b-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(2-methylpyrimidin-5-yl)-(1,2,Agriazoloi|4,3-s|Ipyrimidin-5- 0.0195 0.047 0.2994 amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6- in net 2,4|griazolo!|4,3- c|pyrimidin-5-amine 5-(5-((2 ,3-dihydrobenzofuran-4-yl)methyl)-amino)-vl 2,4|griazoloi4,3-c|pyrimidin-8-yl)picolinonitrile

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-63 ethoxypyridin-3-yl)-(1,2,4)triazolo|4,3-c|pyrimidin-5-0 .0756 0.0686 0.1984 amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1,5-dimethyl- in H-pyrazol-4-yl)-(1,2,4griazolo|4,3-c|pyrimidine -5-amine 8-(6-cyclopropylpyridin-3-yl)-M-(2,3-65(dihydrobenzofuran-4-yl)methyl)-/1,2,4)htriazolo|4,3- 0,0183 0.02 0.1096 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)- 0.0156 0.0447 0.803 (1,2,4)triazolo|4,3-s|Ipyrimidin-5-amine

SHI -(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- pove | ooo | oho 67 (1,2,4|)triazolo|4,3-s|Ipyrimidine- 8-yl)-3,5-dimethyl-1H- 0.0309 0.0902 0.5206 pyrazol-1-yl)ethanol (5-(5-((2,3-dihydrobenzofuran-4-yl)methyl) -amino)- (1,2,4|)triazolo|4,3-s|Ipyrimidin-8-yl)pyridin-2- 0.0197 0.0367 0.478 yl/umorpholino)methanone

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-morpholinopyridin-3-yl)-(1,2,4|triazolo|4,3-c|Ipyrimidine-| 0.182 0, 4769 | MA b-amin

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-methyl-b-70 Kmethylsulfonyl)pyridin-3-yl)-P1,2,4|griazolo!|4,3- 0 .0115 0.0211 0.0839 c|pyrimidin-5-amine 8-(3,5-dimethylisoxazol-4-yl)-M-(5-fluoro-2,3-71 dihydrobenzofuran-4-yl)methyl)- /1,2,4)htriazoloi|4,3- 0,009 0,0189 0,0426 c|pyrimidin-5-amine

Table C (a) (B) (c) (4-(5-((5-fluoro-2,3Z-dihydrobenzofuran-4-yl)-72|methyl)amino)-(1,2,4|triazolo| 4,3-s|Ipyrimidin-8- 0.0093 0.0175 0.0097 yl)/uphenyl)(4-methylpiperazin-1-yl)umethanone

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-methyl-b-73 morpholinopyridin-3-yl)-(1,2,4|triazolo|4,3-c|Ipyrimidine - | 0.0125 0.0174 0.4317 b-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-(2,6-74|dimethylmorpholino)pyridin-3-yl)-1,2,4griazolo|4,3-0, 0896 0.1391 | MA pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-(2-75 methylsulfonyl)ethoxy)phenyl)-I(1,2,4|triazoloi4,3- 0.034 0.0375 0 ,2981 s|pyrimidin-5-amine 8-(4-aminopyridin-3-yl)-M-(2,3-dihydrobenzo-furan-4- 760 bokaminoa 2,4 griazolo!|4,3-s|Ipyrimidine- 5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-(piperazinoto Methods, 2,Agriazoloi|4,3-s|Ipyrimidin-5-amine 8-(6-(difluoromethoxy) )pyridin-3-yl)-M-(2,3-78 dihydrobenzofuran-4-yl)methyl)-/1,2,4)triazolo|4,3- 01034 0.1598 |MA c|pyrimidine-5- amine 5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)-so 2,4|griazolo|4,3-c|Ipyrimidin-8-yl)-M-methylpicolinamide (5- (5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- (1,2,4|)triazolo|4,3-c|Ipyrimidin-8-yl)pyridin-2- 0.0037 0.0088 0.1315 ylUpyrrolidin-1-yl)umethanone

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-81iomorpholinopyridin-3-yl)-(1,2,4|griazolo|4,3- 0.0146 0.0191 0 ,1554 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1-isopropyl-3-82|methyl-1H-pyrazol-4-yl)-P1,2,4)|griazolo|4, 3-c | Ipyrimidine- | 0.0167 0.0309 0.1072 b-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-83 (methoxymethyl)-5-methylpyridin-3-yl)- 0.0105 0.0228 0.1402 (1,2, 4) triazolo|4,3-c|Ipyrimidin-5-amine 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- in 2,4A|griazolo|4, 3-c|Ipyrimidin-8-yl/pyridin-2-yl ethanol

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-vv deti digdo 2,A|griazolo!|4,3-c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-(2-methoxyethyl)pyridin-3-yl)-(1,2,4|htriazoloi|4,3- 0.0111 0.0267 0.0758 c|pyrimidin-5-amine 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 87. 1,2,4)griazoloi|4 ,3-c|Ipyrimidin-8-yl)/pyridin-3- 0.0418 0.0839 0.7071 yl)pyrrolidin-2-one

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(2-88 (dimethylamino)pyrimidin-5-yl)-(1,2,4|triazoloi4,3- 0.0257 0.0347 02375 c|pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(3-(2- (dimethylamino)ethyl)phenyl)-(1,2,4Igriazol!|4,3- 0,0045 0, 0103 0.1009 pyrimidine-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)- 0.0131 0.303 0.6753 (1,2,4)triazolo|4,3-s|Ipyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-91 iomorpholinopyridin-3-yl)-(1,2,4|griazolo|4,3- 0.0099 0.0153 0.0225 c|pyrimidine-5-amine

Table C (a) (b) (c)

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-92 2|morpholinopyridin-3-yl)-(1,2,4|triazolo|4,3-s Ipyrimidine-| |triazolo|4,3-s|pyrimidine-8- 0.0079 0.0125 0.0241 yl)picolinonitrile

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-5-(5-((2,3-dihydrobenzofuran-4-ylmethyl)amino)- 95 (1, 2,4|)triazolo|4,3-s|Ipyrimidin-8-yl)-M, M- 0.0052 0.0128 0.1581 dimethylpicolinamide

Methyl-N-(2,3-dihydrobenzofuran-4-yl))-8-(6-(2- methylpyrrolidin-1-yl)/pyridin-3-yl)-1,2,4-griazolo!|4,3- 0.026 0.0132 0.4286 c|pyrimidin-5-amine

Methyl-4-(5-(5-((2,3-dihydrobenzofuran-4-97 (l)methyl)amino)-(1,2,4|triazolo|4,3-c|pyrimidine-8-0, 0061 0.0086 0.1828 yl)pyridin-2-yl)piperazine-1-carboxylate

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-(3-(methylsulfonyl)propoxy)pyridin-3-yl)- 0.0217 0.0356 1.4173 (1.2 ,4)triazolo|4,3-c|Ipyrimidin-5-amine -(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)- (1,2,4|)triazolo| 4,3-s|Ipyrimidin-8-yl)/pyridin-2-yl)propane-! 0.0042 0.0067 0.1075 -ol 8-(6-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)-M- 100 (2,3-dihydrobenzofuran-4 -yl)methyl)-(1,2,4)griazolo|4,3-| 0.014 0.0315 0.181 c|pyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(6-(4,4-101|dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)-0, 0117 0.0136 0.7614 (1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine 5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 102. |1,2,4)griazolo|4,3-c|Ipyrimidin-8-yl)-M-(2- 0.0339 0.0688 0.285 (dimethylamino)ethyl)-M-methylpicolinamide

Methyl-M-(2,3-dihydrobenzofuran-4-yl)-8-(5-methyl-b-103-pyrrolidin-1-yl)/pyridin-3-yl)-1,2,4)griazolo|4 ,3- 0,7284 0,4306 | MA c|pyrimidin-5-amine d-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 104 |1,2,4)triazolo|4,3-c| Ipyrimidin-8-yl)pyridin-2- 0.0096 0.012 2.4341 yl)upiperazin-2-one d-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 105 (|1,2,A4)triazolo|4,3-c|Ipyrimidin-8-yl)-3-methylpyridin-2- 0.0269 0.0326 2.4238 yl)upiperazin-2-one

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-(2-106 (methylsulfonyl)ethoxy)pyridin-3-yl)- 0.025 0.0341 2.6999 (1,2, 4) triazolo|4,3-c|Ipyrimidin-5-amine d-(2-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 107. |1,2 ,4)triazolo|4,3-c|Ipyrimidin-8-yl)pyridin-2- 0.0124 0.025 0.1612 yl)ethyl)piperazine-1-carbaldehyde 1-(4-(2-(5-(5 -((2,3-dihydrobenzofuran-4-yl)-108 methyl)amino)-(1,2,4)triazolo|4,3-s|Ipyrimidin-8- 0.0067 0.011 0.1734 yl)upyridin- 2-yl)ethyl)piperazin-1-yl)uketen d-(2-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 109 (|1,2,4 )triazolo|4,3-c|Ipyrimidin-8-yl)pyridin-2- 0.0088 0.0137 1.2085 yl)ethyl)piperazin-2-one

Table C (a) (B) (c) -(4-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 110. |1,2,4)griazolo| 4,3-s|pyrimidin-8-yl)pyridin-2- 0.0093 0.0152 0.1239 yl)upiperazin-1-yl)ethanol

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(4-fluoro-6-111Kmethylamino)pyridin-3-yl)-(1,2,4Itriazolo!|4,3- 0,019 0 .0174 0.1395 s|pyrimidin-5-amine m. Idnetylamno with Fluorindic tku, here | olive | tin 112 (dimethylamino)-4-fluoropyridin-3-yl)-(1,2,4|griazolo|4,3 -| 0.0177 0.0176 0.4889 c|pyrimidin-5-amine d-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 113. |1,2 ,4)triazolo|4,3-c|Ipyrimidin-v-yl)pyridin-2-yl)-1,4- 0.0127 0.0157 0.7202 diazepan-1-carbaldehyde 5-(5-((2 ,3-dihydrobenzofuran-4-yl)methyl)-amino)- a diphydroenaofuran mother am amide

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2- ovo Methyl fluoro, 2,4|griazolo|4,3-c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-116 methylpyridin-4-yl)-(1,2,4|triazolo|4,3-c|pyrimidine -5- 0.0047 0.0076 0.0072 amine -(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 117. |1,2,4)griazolo|4 ,3-s|pyrimidin-8-yl)pyridin-2- 0.0235 0.0294 0.4803 yl)uoxazolidin-2-one

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-118 methylpyridin-3-yl)-(1,2,4|triazolo|4,3-c|pyrimidine -5- 0.0101 0.0182 0.0177 amine 8-(6-cyclopropylpyridin-3-yl)-M-(5-fluoro-2,3-

N-hydrobenzofuran-4-ylylmethyl)-I(1,2,4|griazolo|4,3- c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-120 morpholinopyridin-4-yl)-/1,2,4)|griazolo|4,3-s| Ipyrimidine-| 0.0156 0.0256 0.0721 b-amine -(5-((5-fluoro-2,3Z-dihydrobenzofuran-4-121 (|yl)methyl)amino)-(1,2,4|triazolo|4 ,3-c|pyrimidine-8- 0.0134 0.0221 0.0142 yl)benzonitrile -(5-((5-fluoro-2,3Z-dihydrobenzofuran-4- 122 (|l)methyl)amino)-( 1,2,4|triazolo|4,3-s|pyrimidine-8- 0.0192 0.0437 0.1354 yl)benzamide

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(2-123 methylpyridin-3Z-yl)-(1,2,4|triazolo|4,3-c|pyrimidin-5-0 ,0123 0,0234 0,0197 amine 124 dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0,01 0,0154 0,006 c|pyrimidin-5-amine 1-(5-(5 -((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 125 (||1,2,4)griazolo|4,3-c|Ipyrimidin-8-yl)pyridin-2- 0.0085 0.0234 |MA yl)upiperazin-2-one 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 126 (|/1,2,4)griazolo| 4,3-s|Ipyrimidin-8-yl)pyridin-2- 0.0129 0.0172 0.6559 yl)uazetidin-3-ol

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-127|methyl-6-(methylsulfonyl)pyridin-3-yl)- 0.0026 0.0088 0.028 ( 1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-128 methyl-4-(methylsulfonyl)phenyl)-I(1,2,4|Itriazoloi4,3- 0 .0086 0.0165 0.0037 c|pyrimidin-5-amine

Table C (a) (B) (c) (5-(5-((5-fluoro-2,3Z-dihydrobenzofuran-4-yl)-129 methyl)amino)-I(1,2,4)triazolo| 4,3-s|Ipyrimidin-8- 0,0039 0,0084 0,0019 yl)upyridin-2-yl)(pyrrolidin-1-yl)umethanone (5-(5-((5-fluoro-2,3Z -dihydrobenzofuran-4-yl)- 130 methyl)amino)-(1,2,4)triazolo|4,3-c|pyrimidin-8-yl)-4- 0.005 0.0137 0.0013 methylpyridin-2-yl )(pyrrolidin-1-yl-methanone 131 (|yl)methyl)amino)-(1,2,4|triazolo|4,3-c|pyrimidin-8-yl)-M, 0.004 0.0106 0.0033

M,4-trimethylpicolinamide

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1,3,5-132 trimethyl-1H-pyrazol-4-yl)-(1,2,4|griazol !|4,3- 0,0062 0,0102 0,0077 c|pyrimidin-5-amine 4-((5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 133 |1,2,4)griazolo|4,3-c|Ipyrimidin-8-yl)pyridin-2- 0.0087 0.0223 0.1422 yl)umethyl)piperazin-2-one d-(5-(5 -((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 134 |1,2,4)griazolo|4,3-c|pyrimidin-8-yl)pyridin-2- 0.0173 0, 0305 0.1648 yl)ipiperazine-1-carbaldehyde -(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)- 135 (||1,2,4)griazolo|4, 3-c|Ipyrimidin-8-yl)pyridin-2-yl)-M, M- 0.0057 0.0112 0.4214 dimethylpropanamide

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)-8-(4-136 Ctrifluoromethyl)pyridin-3-yl)-P1,2,4)griazolo|4,3-0, 0159 0.0418 0.0804 cypyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(5-(1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine 8-(4-chloro-6 -methoxypyridin-3-yl)-M-(5-fluoro-2,3-138 dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0019 0.0084 0.0072 s| pyrimidine-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-139 methyl-6-(methylsulfonyl)pyridin-3-yl)- 0.0017 0.006 0.0016 (1 ,2,4)triazolo|4,3-c|Ipyrimidin-5-amine 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)-140 methyl)amino)-(1,2 ,4)triazolo|4,3-s|Ipyrimidin-8-yl)-M, M- | 0.0127 0.0551 0.0263 dimethylpicolinamide

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-141 methoxypyridin-3-yl)-(1,2,4)Hygriazolo|4,3-s|Ipyrimidine -5- 0.0171 0.042 0.0351 amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-142|methoxypyridin-3-yl)-(1,2,4)Hygriazoli|4,3-s| Ipyrimidin-5- 0.0024 0.0051 0.0043 amine 8-(1-ethyl-1H-pyrazol-5-yl)-M-(5-fluoro-2,3-143 dihydrobenzofuran-4-yl)methyl) -I(1,2,4Itriazoloi4,3- 0.0181 0.0315 0.0106 c|pyrimidine-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-144|isopropyl-1H-pyrazol-5-yl)-(1,2,4|Itriazoloi|4 ,3- 0,0063 0,0178 0,0683 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-145 methoxypyridin-4-yl)-(1,2,4)Hygriazolo|4,3-c|Ipyrimidine -5- 0.0024 0.0118 0.0052 amine 8-(2,4-dichlorophenyl)-M-(5-fluoro-2,3-dihydrobenzofuran-α-ylylmethyl)-I(1,2,4|griazol |4,3-s|Ipyrimidine-5-amine

Table C (a) (b) (c)

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-147|methyl-1H-pyrazol-4-yl)-11,2,4|griazolo|4,3 -c|Ipyrimidine- | 0.0036 0.0159 0.0113 b-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-148 (|isopropyl-3-trifluoromethyl)-1H-pyrazol-4-yl)- 0.0052 0.018 0.0252 (1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine 8-(1-cyclopropyl-1H-pyrazol-4-yl)-M-(2,3- 149 dihydrobenzofuran- 4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0169 0.0337 02202 c|pyrimidin-5-amine 8-(1-cyclopropyl-1H-pyrazol-4-yl)-M- (5-fluoro-2,3- 150 dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0045 0.007 0.0148 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-151 isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)- 0.0131 0, 0216 0.0086 (1,2,4)triazolo|4,3-s|Ipyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl))-8-(1-methyl-1 H-zwa Metal eV 2,4|griazolo|4,3-s|Ipyrimidin-5-amine

Methyl-M-(2,3-dihydrobenzofuran-4-yl)-8-(1-isopropyl-153B,5-dimethyl-1H-pyrazol-4-yl)-P1,2,4)griazoloi|4, 3- 0.0078 0.0148 0.0073 c|pyrimidin-5-amine 8-(6-(difluoromethyl)pyridin-3-yl)-M-(2,3- 154 dihydrobenzofuran-4-yl)methyl)- I(1,2,4Itriazoloi4,3- 0.0201 0.0369 0.0968 c|pyrimidine-5-amine

Methyl-N-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-155 methoxy-2-methylpyridin-3-yl)-(1,2,4|griazolo!|4, 3- 0.017 0.0453 0.078 c|pyrimidin-5-amine 8-(6-amino-2-methylpyridin-3-yl)-M-(5-fluoro-2,3-156 dihydrobenzofuran-4-yl)methyl) -I(1,2,4Itriazoloi4,3- 0,004 0,0173 0,0261 c|pyrimidin-5-amine 8-(2-chloro-4-fluorophenyl)-M-(5-fluoro-2,3- 157 dihydrobenzofuran -4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0223 0.0463 0.4454 c|pyrimidin-5-amine -(4-(5-((5-fluoro-2,Z -dihydrobenzofuran-4-yl)-158 methyl)amino)-(1,2,4)triazolo|4,3-c|pyrimidin-8-yl)-3,5- 0.0051 0.0096 0.0067 dimethyl -1H-pyrazol-1-yl) ethanol

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-(2-159 methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)- 0.005 0.0103 |M/A (1,2,4)triazolo|4,3-s|Ipyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-160 Ctrifluoromethyl)pyridin-3-yl)-(1,2,4)griazolo|4,3- 0 .0059 0.0113 | MA cypyrimidine-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-161|fluoro-b-methoxypyridin-3-yl)-(1,2,4A|Itriazoloi|4, 3- 0.0036 0.0098 |M/A c|pyrimidin-5-amine 8-(3-chloropyridin-4-yl)-M-(5-fluoro-2,3-162 (dihydrobenzofuran-4-yl) methyl)-I(1,2,4Itriazoloi4,3- 0.0057 0.0211 0.0273 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(3-163 methylpyridin-4-yl)-(1,2,4|triazolo|4,3-c|pyrimidine -5- 0.0041 0.0109 | MA amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(6-164 |fluoro-2-methylpyridin-3-yl)-(1,2,4A|Itriazoloi|4, 3- 0.0042 0.0139 |M/A c|pyrimidin-5-amine

Table C (a) (b) (c)

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-165 |fluoro-2-methylphenyl)-(1,2,4)triazolo|4,3-s| pyrimidine-5- 0.0045 0.0074 | MA amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)-8-(2-166 Ctrifluoromethyl)pyridin-3-yl)-P1,2,4)griazolo|4,3-0, 0111 0.031 0.0266 c|pyrimidine-5-amine tag. pdvobeyuofura i yametnya tela ooo | tin | tin 167 |dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0033 0.0052 0.0393 c|pyrimidin-5-amine 8-(2-(difluoromethyl)pyridin-3- yl)-M-(5-fluoro-2,3-168(dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0046 0.0112 0.002 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-169 methyl-1H-pyrazol-5-yl)-I1,2,4|griazoloi|4,3- c|Ipyrimidine- | 0.0045 0.0066 0.0029 b-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-170 methyl-3-trifluoromethyl)-1H-pyrazol-4-yl)- 0.0107 0.0121 0.0232 (1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine

IM-((5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-171 (|yl)methyl)amino)-(1,2,4|triazolo|4,3-c|pyrimidine- 8- 0.006 0.0073 0.0265 yl)pyridin-2-ylmethyl)acetamide 8-(1,5-dimethyl-1H-pyrazol-4-yl)-M-(5-fluoro-2,3- 172 |dihydrobenzofuran -4-yl)methyl)-I(1,2,4Altriazoloi4,3- 0.0066 0.0071 0.0044 cIpyrimidin-5-amine 8-(6-cyclopropyl-4-methylpyridin-3-yl)-M- (5-fluoro-2,3- 173 dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0075 0.0077 0.0152 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-174)methoxypyrimidin-5-yl)-(1,2,4)triazolo|4,3-s| Ipyrimidine- | 0.0047 0.0062 0.0042 b-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-175 methoxy-4-methylpyrimidin-5-yl)-1,2,4Hygriazolo|4,3-0, 0063 0.0092 0.0034 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-176 methylpyrimidin-5-yl)-(1,2,4)Hygriazolo|4,3-s|Ipyrimidine -5- 0.0059 0.0083 0.0046 amine 8-(2,3-dimethylpyridin-4-yl)-M-(5-fluoro-2,3-177|dihydrobenzofuran-4-yl)methyl)-I (1,2,4Altriazoloi4,3- 0,0038 0,0044 0,0044 s|pyrimidin-5-amine 178 (|l)methyl)amino)-(1,2,4|triazolo|4,3-s| Pyrimidin-8-yl)-3- 0.0054 0.007 0.0114 methylbenzonitrile 8-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-M-(5- 179 Ifluoro-2, 3-Dihydrobenzofuran-4-yl)methyl)- 0.0124 0.0161 0.0091 (1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-180|fluoro-3Z-methylpyridin-4-yl)-(1,2,4|Itriazoloi|4, 3- 0.0073 0.0079 0.0124 c|pyrimidin-5-amine 8-(2-(difluoromethyl)-3-methylpyridin-4-yl)-M-(5-fluoro-2,3- 181 dihydrobenzofuran- 4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0026 0.006 0.0208 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-182. (fluoromethyl)-3-methylpyridin-4-yl)-11,2,4)griazolo|4 .3- 0.0031 0.0056 0.0025 c|pyrimidin-5-amine

Table C (a) (b) (c)

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-183 |fluoro-5-methylpyridin-4-yl)-(1,2,4|Itriazoloi|4, 3- 0.0048 0.0081 0.0106 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(5-184 methyl-2-trifluoromethyl)pyridin-4-yl)- 0.0054 0.0132 0.0777 (1,2,4)triazolo|4,3-s|Ipyrimidin-5-amine tv. Priforyutyatutnyk I tot oon | words | base 185 Ctrifluoromethyl)pyridin-4-yl)-P1,2,4)griazolo|4,3- 0.0044 0.0067 0.0468 pyrimidine-5-amine (28)-1-(4-(5-( (5-fluoro-2,3-dihydrobenzofuran-4-186 (|yl)methyl)amino)-(1,2,4|)triazolo|4,3-c|Ipyrimidin-8-yl)-3,5- 0.0035 0.006 0.0068 dimethyl-1H-pyrazol-1-yl) propan-2-ol (25)-1-(4-(5-((5-fluoro-2,3-dihydrobenzofuran-4- 187 ( |yl)methyl)amino)-(1,2,4|)triazolo|4,3-c|Ipyrimidin-8-yl)-3,5- 0.0082 0.0125 0.012 dimethyl-1H-pyrazol-1- il) propan-2-ol

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1-188 (|isopropyl-5-methyl-1H-pyrazol-4-yl)-P1,2,4 |griazoloi|4,3- 0,0023 0,0038 0,0036 c|pyrimidin-5-amine -(4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)-189 methyl) amino)-(1,2,4)triazolo|4,3-c|pyrimidin-8-yl)-5- 0.0042 0.0087 0.0052 methyl-1H-pyrazol-1-yl)ethanol -( 4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)-190 methyl)amino)-(1,2,4)triazolo|4,3-c|pyrimidin-8-yl)- 3- 0.0045 0.0171 0.0025 methyl-1H-pyrazol-1-yl)ethanol 8-(4--(difluoromethyl)pyrimidin-5-yl)-M-(5-fluoro-2,3-

N-hydrobenzofuran-4-ylmethyl)-I(1,2,4|griazolo|4,3- c|pyrimidin-5-amine 8-(1-cyclopropyl-1H-pyrazol-5-yl)-M-( 5-fluoro-2,3- 192

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-193 Kfluoromethyl)pyridin-3-yl)-(1,2,4|triazoloi|4,3- 0.004 0.013 0.0054 c|pyrimidin-5-amine 8-(2,5-dimethylpyridin-4-yl)-M-(5-fluoro-2,3-194 dihydrobenzofuran-4-yl)methyl)-I(1, 2,4Itriazoloi4,3- 0,0024 0,007 0,0241 c|pyrimidin-5-amine 8-(1,3-dimethyl-1H-pyrazol-4-yl)-M-(5-fluoro-2,3- 195 (dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0059 0.0116 0.0024 c|pyrimidin-5-amine tw. (dihydrobenzofuran-4-yl)methyl)-I(1,2,4Itriazoloi4,3- 0.0036 0.0082 0.0263 c|pyrimidin-5-amine 8-(6-(difluoromethoxy)-4-methylpyridine-3 -yl)-M-(5-fluoro-197 r.3-dihydrobenzofuran-4-yl)umethyl)-P1,2,4|Igriazolo|4,3- | 0.0022 0.0057 0.0149 c|pyrimidine -5-amine 8-(2-(difluoromethyl)-5-methylpyridin-4-yl)-M-(5-fluoro-2,3- 198 (dihydrobenzofuran-4-yl)methyl)-I (1,2, 4-Itriazoloi4,3- 0,0044 0,0173 0,0078 c|pyrimidin-5-amine 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-199 (|l)methyl)amino)-( 1,2,4|triazolo|4,3-s|pyrimidin-8-yl)-M, 0.0042 0.0072 0.005

M,b-trimethylpicolinamide 8-(33-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-M-(5-200 Ifluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-0 .0075 0.0095 0.003 (1,2,4)triazolo|4,3-c|Ipyrimidin-5-amine

Table C

NSS PN sleep RKS Ks ek

Pr. i Name IYUPAK ISvo (MKM)| ISvo (MKM) ISso (MKM) 8-(2-(difluoromethyl)-6-methylpyridin-3-yl)-M-(5-fluoro-2,3-201 dihydrobenzofuran-4-yl)methyl)-I(1 ,2,4Itriazoloi4,3- 0,0059 0,0073 0,0036 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-202 (pyridazin-4-yl)-(1,2,4|triazolo|4,3-s|Ipyrimidin-5 -amine 0.0096 0.0187 0.0206

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-7-methyl- 203 IV-(2-methylpyridin-3-yl)-(1,2,4|Itriazolo|4,3 -c|Ipyrimidin- | 0.0424 0.4385 |MA b-amine -(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)- 204 |methyl)amino)-(1,2, 4) triazolo|4,3-c|Ipyrimidin-8-yl)-2- 0.0106 0.0193 0.0103 methylpyridine 1-oxide

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-205|pyrazin-2-yl)-1,2,4Itriazolo|4,3-cIpyrimidin-5-amine 0.0073 | 0.0082 | 0.0167

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-206 (pyrimidin-5-yl)-(1,2,4)griazolo|4,3-s|Ipyrimidin-5 -amine 0.0091 0.0095 0.0159

Methyl-M-(5-fluorobenzofuran-4-yl))-8-(2-methylpyridin-207Vl)-11,2,A)triazolo4,3-cypyrimidin-5-amine 0.0795 | 01817 | 0.0036

M-(benzofuran-4-ylmethyl)-8-(4-208 (|(dimethylamino)methyl)phenyl)-I(1,2,4|triazolo|4,3- 0.0062 0.0127 0.0190 s |pyrimidine-5-amine

M-(benzofuran-4-ylmethyl)-8-(4-(4-methyl-piperazin-1-209 | luphenyl)-/1 2 AIgriazoloi4 3-cypyrimidin-5-amine 0.0369 | 0.0290 |) 01173

M-(benzofuran-4-ylmethyl)-8-(4-(1-(pyrrolidin-1-210|luethyluphenyl)-/1,2,Altriazolog, 3-cypyrimidin-b-amine | 00185) 0214 MA

M-(benzofuran-4-ylmethyl)-8-(6-(4-methyl-piperazin-1-211 yl)pyridin-3-yl)-(1,2,4|griazoloi|4,3-s|Ipyrimidine -5-amine 0.0322 00288 MA gla. 00338 | MA

M-(benzofuran-4-ylmethyl)-8-(pyridin-3-yl)- 213.4 2 AIgriazolog,3-cypyrimidin-5-amine 00366 | 00256 | MA

M-(benzofuran-4-ylmethyl)-8-(4-(methyl-214 sulfonyl)phenyl)-(1,2,4|griazolo|4,3-c|Ipyrimidin-5-amine 0.0374 00225 | MA

M-(benzofuran-4-ylmethyl)-8-(4-(isopropylsulfonyl)- 215. |phenyl)-1,2,Altriazolo|4,3-cypyrimidin-5-amine 00203 | 00212 | MA (4-(5-(benzofuran-4-ylmethyl)amino)-(1,2,4|Hygriazolo|4,3- 216 c|pyrimidin-8-iluphenyl) (pyrrolidin-1-ylumethanone 01315 olvza MA 217 Mobenzofuran epylmethyl in phenyl 2 triazologs in. О4в32 | 0113 с|pyrimidin-5-amine

M-(benzofuran-4-ylmethyl)-8-(pyridin-4-yl)- 218.14 2 aItriazolog,3-cypyrimidin-5-amine 00386 | 0.0263 | MA 8-(4--(dimethylamino)methyl)phenyl)-M-(5-fluoro-219 benzofuran-4-yl)methyl)-(1,2,4)griazoloi|4,3-s|Ipyrimidine-| 0.0065 0.0068 0.0079 b-amine

M-(benzofuran-4-ylmethyl)-8-(4-(1-methyl-piperidin-4-220 (|Il)sulfonyl)phenyl)-11,2,4)triazolo|4,3-s|pyrimidine- 5- 0.0141 0.0216 0.4667 amine 221 pyrimidine-5-yl)-I1,2,Altriazolo4,3-sipyrimidin-5-amine 0.0091 0.0095 0.0159 8-(4,6-dimethylpyridine -3-yl)-M-(5-fluoro-2,3- 222 Idihydrobenzofuran-4-yl)methyl)-I(1,2,4Htriazoloi4,3- 0.0117 0.0140 0.0576 c|pyrimidin- 5-amine 8-(6-(dimethylamino)methyl)-2-methylpyridin-3-yl)-M-(5-223 Ifluoro-2,3-dihydrobenzofuran-4-yl)umethyl)- 0.0084 0.0184 0.0014 (1,2,4)triazolo|4,3-s|Ipyrimidin-5-amine

Table C (a) (B) (c) 8-(6-ethyl-4-methylpyridin-3-yl)-M-(5-fluoro-2,3- 224 Idihydrobenzofuran-4-yl)methyl)-I( 1,2,4Itriazoloi4,3- 0.0015 0.0019 0.0022 c|pyrimidin-5-amine 8-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-M-(5-fluoro-225 r. 3-dihydrobenzofuran-4-yl)methyl)-P1,2,4|Hygriazolo|4,3- | 0.0075 0.0106 0.0045 c|pyrimidin-5-amine sov. pdubecofuran iletnt (I riazoloi, oooze | tin | ote 226 dihydrobenzofuran-4-yl)methyl)-I(1,2,4Igtriazoloi4,3- 0.0039 0.0050 0.0061 s|pyrimidin-5-amine (4- (5-((5-fluoro-2,3Z-dihydrobenzofuran-4-227|l)methyl)amino)-(1,2,4|triazolo|4,3-c|pyrimidin-8-yl)-1- 0.0061 0.0075 0.0091 methyl-1H-pyrazol-5-yl)umethanol 8-(2-chloro-5-methylpyridin-4-yl)-M-(5-fluoro-2,3- 228 dihydrobenzofuran -4-yl)methyl)-I(1,2,4Htriazoloi4,3- 0.0082 0.0090 0.0292 c|pyrimidin-5-amine 8-(6-ethyl-2-methylpyridin-3-yl)- M-(5-fluoro-2,3- 229 Idihydrobenzofuran-4-yl)methyl)-I(1,2,4Htriazoloi4,3- 0.0059 0.0067 0.0027 c|pyrimidin-5-amine

Methyl-N-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(2-230 methoxy-33-methylpyridin-4-yl)-P1,2,4|griazolo!|4,3 - 0.0129 0.0245 0.0252 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-

ED 2,4|griazolo|4,3-s|pyrimidine-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(5-232 methylpyridin-33-yl)-(1,2,4|triazolo|4,3-c|pyrimidine -5- 0.0062 0.0131 0.0133 amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4- 233 methyl-1H-imidazol-1-yl)-11,2,4|griazoloi|4,3- c|Ipyrimidine-| 0.0039 0.0115 0.0020 b-amine (5-(5-((5-fluoro-2,3Z-dihydrobenzofuran-4-yl)- svv nettivno 2,4|griazolyi4,3-s|Ipyrimidine-8 - yl)upyridin-2-yl)umethanol 8-fluoro-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2,4-dimethyl-1H-imidazol-1-yl) )-M-(5-fluoro-2,3- 236 Idihydrobenzofuran-4-yl)methyl)-I(1,2,4Htriazoloi4,3- 0.0102 0.0232 0.0076 c|pyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1 H- 237 MethylM -yl)-(1,2,4)triazolo|4,3-s|Ipyrimidin- 5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(3-238 methyl-1H-1,2,4-triazol-1-yl)-1,2,4| griazoloi|4,3- 0,0047 0,0144 0,0179 cIpyrimidin-5-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(4-

KE H-pyrazol-1-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-b-amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1H-glo Methyl)-1,2,4)griazolo|4,3-c|Ipyrimidin-5 -amine

Methyl-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl))-8-(1 H- 241. 1,2,4-triazol-1-yl)-(1,2,Agriazoloi|4 ,3-s|Ipyrimidine-5- 0.0113 0.0300 0.0284 amine

B-fluoro-4-((8-(2-methylpyridin-3-yl)-1,2,4|htriazoloi|4,3- 242 Is|pyrimidin-5-yl)amino)methyl)-2,3- dihydrobenzofuran-3-| 0.0138 0.0500 0.0634 ol

Table C (a) (b) (c)

B-fluoro-4-((8-(2-(hydroxymethyl)pyridin-3-yl)- 243 |/1,2,4)griazolo|4,3-c|Ipyrimidin-5-yl)amino)methyl) -2,3- 0,0154 0,0590 0,0409 dihydrobenzofuran-3-ol -(5-((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4- 244 |l)methyl)amino)- (1,2,4|triazolo|4,3-c|pyrimidin-8-yl)-2- 0.0117 0.0389 0.2415 methylpyridine 1-oxide 8-(1,2-dimethyl-1H-imidazol- 5-yl)-M-(5-fluoro-2,3-245 dihydrobenzofuran-4-yl)methyl)-I(1,2,4Htriazoloi4,3- 0,0672 02232 | MA c|pyrimidin-5-amine

Table 4 below shows the antiproliferative activity values (IC values) against KAKRAB422 B-cell lymphoma cells after 14 days of treatment for the following examples

Table 4 6 | 00002 ( 78 | 00006 2 ( 79 | yuklo00006 Z

Accordingly, the compounds of the present disclosure have been found to inhibit EEO and therefore can be used in the treatment of diseases or disorders associated with EEO and PKC2, including but not limited to diffuse large B-cell lymphoma (0 ALL), follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rod-shaped tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumors including neuroblastoma, glioma , glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell cancer, rectal cancer, thyroid cancer glands, parathyroid tumors, uterine tumors, and soft tissue sarcomas selected from rhabdomyosarcoma (KM5), Kaposi's sarcoma, synovial sarcoma, osteosarcoma, and sarcoma and Ewing.

M. PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS

Compounds of the present invention are typically used in the form of a pharmaceutical composition (eg, a compound of the present invention and at least one pharmaceutically acceptable carrier). "Pharmaceutically acceptable carrier (diluent or excipient)" refers to media commonly used in the art to deliver biologically active substances to animals, particularly mammals, including commonly defined as safe (ZKA5) solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, buffering agents (eg, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), leavening agents, lubricants, sweeteners, flavors, dyes, etc. and their combinations, known to the expert (see, for example, APep, I.M., Ug. ei aiYi., Vetipdiop: Tne bsiepse apa Rgasiise oi

Rpagtasu (2 Moishtev), 22pa Eaiiop, Rpaptasetshiysa! Rgez5 (2012). According to the present invention, solvates and hydrates are considered to be pharmaceutical compositions comprising a compound according to the present invention and a solvent (i.e. solvate) or water (i.e. hydrate).

Formulations can be prepared using standard dissolution and mixing procedures. For example, a drug substance (ie, a compound of the present invention or a stabilized form of the compound (eg, a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.

The compounds of this disclosure may be administered for any of the uses described herein by any suitable means, e.g., orally, in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, by such methods as subcutaneous, intravenous, intramuscular or intrathoracic injection or infusion methods (for example, in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including introduction into the nasal membranes, such as by spraying by inhalation; locally, for example, in the form of a cream or ointment; or rectally, for example, in the form of suppositories. They may be administered individually, but are usually administered with a pharmaceutical carrier selected based on the chosen route of administration and in accordance with standard pharmaceutical practice.

A compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controlled dosage of the drug and to provide the patient with a refined and easily controlled product. The mode of administration for the compounds of the present disclosure will, of course, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and the method and route of administration; type, age, gender, state of health, diseases and body weight of the recipient; nature and extent of symptoms; type of parallel treatment; frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect. The compounds of this disclosure may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two, three, or four times per day.

In some cases, it may be preferable to administer a compound of the present invention in combination with at least one additional pharmaceutical (or therapeutic) agent, such as other

Anticancer agents, immunomodulators, antiallergic agents, antinausea agents (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

The term "combination therapy" refers to the administration of two or more therapeutic agents for the treatment of a therapeutic disease, disorder or condition described herein. Such administration involves co-administration of these therapeutic agents substantially simultaneously, for example in a single capsule having a fixed ratio of active ingredients.

Also, such administration includes co-administration in multiple or separate containers (eg, capsules, powders, and liquids) for each active ingredient. A compound of the present disclosure and additional therapeutic agents may be administered by the same route of administration or by different routes of administration. Powders and/or liquids may be reconstituted or diluted to the desired dosage prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent sequentially, at approximately the same time or at different times. In either case, the treatment regimen provides the beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.

Common chemotherapeutic agents considered for use in combination therapy include anastrozole (AgitidexF), bicalutamide (SazodexF), bleomycin sulfate (ViepohapeF), busulfan (MuiegapF), injectable busulfan (VizyMexF), capecitabine (HeodafF), MaA-pentoxycarbonyl -5-deoxy-5-fluorocytidine, carboplatin (RagariaipF), carmustine (VISMOF), chlorambucil (IgeyKegapF), cisplatin (Riayipoi!F), cladribine (IeviaypF), cyclophosphamide (SuyuhapF or MeozagfF), cytarabine, cytosine arabinoside (Suyozag- SHF), cytarabine liposome injection (Oerosui"), dacarbazine (OTIS-boteF), dactinomycin (Actinomycin O, Soztedap), daunorubicin hydrochloride (SegibidipeF), daunorubicin citrate liposome injection (RaipoHoteFf), dexamethasone, docetaxel (TahoiegefF) , doxorubicin hydrochloride (AagiatusipF),

VirekhF), etoposide (MerezidF), fludarabine phosphate (RishdagaF), 5-fluorouracil (AagisiiF,

EtidexF), flutamide (EshehipF), tezacitibin, gemcitabine (difluorodeoxycytidine), hydroxyurea (NudgeaF), idarubicin (IdatusipF), ifosfamide (IREXF), irinotecan (SatriozagfF), I -asparaginase (EI 5RAKF), leucovorin calcium, melphalan (AiIKegapF) . with a carmustine implant (SiiadeIF), tamoxifen citrate (MoiYmadexFf),

teniposide (MytopF), 6-thioguanine, thiotepa, tirapazamine (Tiga7opef), topotecan hydrochloride for injection (NusatrilipF), vinblastine (MeIbapF), vincristine (OpsomipF), and vinorelbine (MameiBbipef).

Particularly interesting anticancer agents for combination with the compounds of the present disclosure include:

Inhibitors of cyclin-dependent kinase (SOC): (Spep, 5. ei ai., Mai Sei! Vio!., 12(11):1108-14 (2010); 7epa, H. ei ai., SeiI Susie, 10( 4):579-83 (2011)) alloisin A; alvocidib (also known as flavopiridol or HME-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-((35,4H8)-3-hydroxy-1-methyl-4-piperidinyl|-4-chromenone , and described in US patent No. 5,621,002); crizotinib (RE-02341066,

SAB 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-K2B, /-35)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl|-AN-1-benzopyran-4-one hydrochloride (P276 -00, SAB 920113-03-7);. 1-Methyl-5-|(2-(5- (trifluoromethyl)-1H-imidazol-2-yl|-4-pyridinyl|oxy|-M-(4-(trifluoromethyl)phenyl|-1 H-benzimidazole- 2 -amine (KAB265, САБ5Б 927880-90-8); indisulam (Е7070); roscovitine (СУС202); b-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2- ylamino)-8-H-pyrido|2,3-4|pyrimidin-7-one hydrochloride (РООЗ332991); dinaciclib (5СН727965); M-(5-I(b-tert-butyloxazol-2-ilumethylhigio|)hiazol- 2-yl|Ipiperidine-4-carboxamide (BM5 387032, CA5Z 345627-80-7); 4-((9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido|5,4-4(2 |benzazepin-2-yl|Iiamino|-benzoic acid (MI M8054, CA5 869363-13-3); 5-I3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5- yl|-M-ethyl-4-methyl-3-pyridinemethanamine (АС-024322, CA5 837364-57-5); M-(piperidin-4-yl)amide 4-(2,6-dichlorobenzoylamino)-1H-pyrazole -3-carboxylic acid (AT7519, CA5 844442-38-2); 4--2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl|-M-(4--"methylsulfonyl)phenyl |-2-pyrimidinamine (А2ХО5438, СА5 602306-29-6); palbociclib (РО 0332991); and (2Е, 3к)-3-Ц2-Ц(З-И5(А)И-5-cyclopropylsa lphonimidoyl|-phenyl|amino|-5-(trifluoromethyl)-4-pyrimidinyl|oxy|-2-butanol. (VAU 10000394).

Inhibitors of the control point kinase (SNK): (Mch, 2. ei ai., Seii YuOeain Oineg., 18(11):1771-9 (2011)) 7-Hydroxystaurosporin (OSM-01); 6b-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3)-3-piperidinyl-pyrazolo|1,5-a|Ipyrimidin-7-amine (ЗСНО0О0776, SAZ 891494-63 -6); M-((5)-piperidin-3-yl|amide. 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid (А2О7762, SAZ 860352-01-8); 4-

I(35)-1-azabicyclo(|2,2,2|oct-3-yl)amino|-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one ( SNIV 124, CA5 405168-58-3); 7-aminodactinomycin (7-AABB), isogranulatimide, debromohymenialdizin; M-

Zo 15-Bromo-4-methyl-2-(25)-2-morpholinylmethoxy|-phenyl|-M'-(5-methyl-2-pyrazinyl) erucine (I M2603618, CA5 911222-45-23u; sulforaphane (CA5 4478-93-7, 4A-Methylsulfinylbutyl ether of isorodanoic acid); 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo|1,2,3-1d4:32,1-

KCpyrroloiY3,4-C(I1 b|benzodiazocine-1,3(2H)-dione (ZV 218078, SAB 135897-06-2); and TAT-5216A (USEKKEKOKEKKI UKZRAMREMI), and SRBOBI ((a-Vra)zmv( a-Rpe-E5ua-Spa)gttatt) and (scK)-a-amino-N-(5,b-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H -pyrrolo|4,3,2-eP(2,Z|benzodiazepin-8-yl|-cyclohexaneacetamide (RE-047 7736).

Inhibitors of protein kinase B (RKV) or AKT: (Koiapazaki!, M., Sei!Yi Susie, 12(2):202-3 (2013);

Spep V. ei ai., Seiyi Susie, 12(1):1112-21 (2013)). 8-(4-(1-aminocyclobutyl)phenyl|-9-phenyl-1,2,4-triazolo|3,4-CH1,b|Inaphthyridin-Z(2H)-one (MK 2206, CA5 1032349-93- 1); perifosine (KEHO401); 4-dodecyl-M-1,3,4-thiadiazol-2-yl-benzenesulfonamide (RNT-427, SAB 1191951-57-1); 4-(2-(4-amino- 1,2,5-oxadiazol-3-yl)-1-ethyl-7-((35)-3-piperidinyl-methoxy|-1H-imidazo|4,5-c|Ipyridin-4-yl|- 2- methyl-3-butyn-2-ol (55K690693, SAB5B 937174-76-0); 8-(1-hydroxyethyl)-2-methoxy-3-|(4-methoxyphenyl)methoxy|-6EN-dibenzoi|, d |pyran-b6-one (palomid 529, P529 or 565-00529); tricyrbin (6b-amino-4-methyl-8-(8-Y-ribofuranosyl)-4H, 8H-pyrroloi|4,3,2-de |pyrimido|4,5-c|Ipyridazine); (а5)-а-((5-(3-Methyl-1H-indazol-5-yl)-Z-pyridinyl|oxy|methyl|-benzenetanamine (АЕ74563, СА 552325-73-23); 4-(methyl(4-chlorophenyl)|-1-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)-4-piperidinamine (ССТ128930,

SAB 885499-61-6); 4-4-(4-chlorophenyl)|(4-(1 H-pyrazol-4-iluphenyl|-piperidine (AT7867, SAZ 857531-00-1); and archexin (ЭХ-0201, CA5 663232-27-7) .

S-VAK inhibitors: (Spapo, S. eyi a!., Sapseg Seyi!, 19(1):86-100 (2011)) sorafenib (MekhamagF); 3-(Dimethylamino)-M-(3-(4-hydroxybenzoyl)amino|-4-methylphenyl|-benzamide (7M336372, CA5 208260-29-1); and 3-(1-cyano-1-methylethyl)-M -I3-(3,4-dihydro-3-methyl-4-oxo-b6-quinazolinyl)amino|-4-methylphenyl|-benzamide (A2628, SAB5 1007871-84-2).

Inhibitors of phosphoinositide-3-kinase (RIZK): (Sop7aiye7, M. ei ai., Sapseg Rev., 71(6): 2360-2370 (2011)).. 4-(2-(1H-indazol-4-yl) )-6-(4-(methylsulfonyl)piperazin-1-yl|methylhieno|3,2-NIpyrimidin-4-yl|morpholine (also known as 5OS 0941 and described in PCT publications M/O09/036082 and

MO09/055730); /2-Methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo|4,5-c)quinolin-1-yl|Iphenyl|Ipropionitrile (also known as VE2235 or MMP-VE7 235 and described in the PCT publication

MO06/122806); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)/pyridin-2-amine (also known as VKM120 or MMP-VKM120 and described in PCT Publication Mo U/O2007/084786); 60 tozasertib (UKb80 or MK 0457, CA5 639089-54-6); (52)-5-((4-(4-Pyridinyl)-6-quinolinyl|methylene-

2,4-thiazolidinedione (535K1059615, CA5 958852-01-2); (1Е, 45, 4ав, 5Е, bab, Zav)-5-(acetyloxy)-1-Kdy-2-propenylamino)methylene-4,4a, 5,6,ba, 8,9,9a-octahydro-11- hydroxy-4-(methoxymethyl)-4a, ba-dimethyl-cyclopenta|5,6bInaphto|1,2-c|pyran-2,7,10(1H)-trione (РХ8Ф6б6, SAB 502632-66-8); 8-

Phenyl-2-(morpholin-4-yl)u-chromen-4-one (17294002, CA5 154447-36-6); 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido(2,3-4|Ipyrimidin-7(8H)-one (ZAK 245409 or ХИ 765); 1,3 -dihydro-8-(6-methoxy-3-pyridinyl)-3-methyl-1-I(4-(1-piperazinyl)-3-trifluoromethyl)phenyl|-2H-imidazoi|4,5-siquinoline- 2-one, (27)-2-butenedioate (1:11) (VST 226); 5-Fluoro-3-phenyl-2-((15)-1-"9H-purin-6-ylamino)ethyl|- 4(ZH)-quinazolinone (CA 101); 2-amino-M-I(3-(M-I3-(2-chloro-5-methoxyphenyl)aminoquinoxalin-2-yl|isosulfamoyl|phenyl|-2-methylpropanamide ( 5AK 245408 or XI. 147); and (5)-Pyrrolidin-1 2-dicarboxylic acid 2-amide 1-(/4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethyl) -ethyl)-pyridin-4-yl|-thiazol-2-yl)/-amide) (VMI-719).

Inhibitors of VSI-2: (Vediiyip, MM. ei a!., Sapseg Seiyi, 23(5):677-92 (2013)) 4-I4-C2-(4-chlorophenyl)-5,5-dimethyl-1- cyclohexen-1-yl|methyl/|-1-piperazinyl|-M-(4-(1 2K)-3-(4-morpholinyl)-1-

Cphenylthio)methyl|propylamino|-3-Ctrifluoromethyl)sulfonyl|Ifenyl|-sulfonyl|benzamide (also known as AVT 263 and described in PCT publication UM/O09/155386); tetrocarcin A; antimycin;

Gossypol ((-) VI 193); obatoclax; Ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromone-3-carboxylate (НА14-1); Oblimersen (53139, SepazepzeF); Vak VZ peptide; (-)-

Gossypol acetic acid (AT 101); 4-I4-K(4-Chloro|1,1"-biphenyl|-2-ilumethyl/|-1-piperazinyl|-M-(4-(1B)-3-(dimethylamino)-1-Cphenylthio)methyl |propyl|amino|-Z-nitrophenyl|sulfonyl|-benzamide (АВТ 737, СА5 852808-04-9) and Navitoklax (АВТ 263, САЗ 923564-51-6).

Inhibitors of mitogen-activated protein kinase (MEK): (Spapo, S.U. ei aI., Sapseg Seyi!, 19(1):86-100 (2011)) ХИ-518 (also known as OS-0973, base Mo. 1029872-29-4, available from ACC

Sogr.); selumetinib (5-(4-bromo-2-chlorophenyl)amino|-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H- benzimidazole-b-carboxamide, also known as A2O6244 or AKKU 142886, described in publications

PCT Mo UMO2003077914); benimetinib (2-hydroxyethoxy)amide (6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3-H-benzoimidazole-5-carboxylic acid), also known as MEK162, CA5 1073666-70-2, described in the publication of PCT Mo UUO2003077914); 2-(2-Chloro-4-iodophenyl)amino|-M-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-14040 or PO184352 and described in PCT publication Mo MMO2000035436); M-(2A)-2,3-dihydroxypropoxy|-3,4-difluoro-2-((2-

Zo fluoro-4-iodophenyl)amino|-benzamide (also known as РООЗ3З25901 and described in PCT publication Mo

MO2002006213); 2,3-bi(amino(2-aminophenyl)thio|methylene|-butanenitrile (also known as 00126 and described in US Pat. No. 2,779,780); M-13,4-difluoro-2-(2-fluoro-4-iodophenyl) )amino|-6-methoxyphenyl|-1-(28)-2,3-dihydroxypropyl|-cyclopropanesulfonamide (also known /- as

VOEAT119 or VAU869766 and described in the publication PCT Mo UMO2007014011); (35, 48, 57, 85, 95, 11E)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecin- 1,7(8H)-dione| (also known as Eb201 and described in the PCT publication

MO UMO2003076424); 2'-amino-3'-methoxyflavone (also known as PO9U8VO59, available from Viaip

St.N. and So. KO, Germany); vemurafenib (RI Kh-4032, SAbB 918504-65-1); (B8)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridoi|2,3-4|pyrimidine-4, 7(ZH, 8H) -dione (TAK-733, SAB5 1035555-63-5); pimasertib (AB 703026, CA 1204531-26-9); trametinib dimethylsulfoxide (55K-1120212, SAbB 1204531-25-80);. 2-(2-fluoro-4-iodophenylamino)-M-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AO 8330); and 34-difluoro-2-K2-fluoro-4-iodophenyl)amino|-M-(2-hydroxyethoxy)-5-(3-oxo-P,2|oxazinan-2-ylylmethyl|benzamide (CH 4987655 or Ko 4987655 ).

Aromatase inhibitors: (Rayiga)ia, T. eyi a!., 5si. Tgapvi Mea., 6(229):229 gad (2014)) exemestane (AgotabvipF); letrozole (Getagaf); and anastrozole (AgitidexF).

Inhibitors of topoisomerase I!: (Vai, 5). hey ay., Seii! Rgoiiyi., 47(3):211-8 (2014)) Etoposide (MP-16 and

Etoposide phosphate, Torosagb, Mereziy" and EtuororpozF); teniposide (MM-26, MytopF); and tafluposide.

ZKS inhibitors: (Nerraga, Y., Opsodepe, 30(3):301-12 (2011)) dasatinib (Zrgusei!F); saracatinib (A200530, SAB 379231-04-6); bosutinib (5KI 606, SAB 380843-75-4);. 5-(A-(2-ethoxy(4-morpholinyl)|phenyl|-M-(phenylmethyl)-2-pyridineacetamide (КХ2-391, САБ5 897016-82-9); and 4-(2-Chloro-5- methoxyanilino)-b-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-quinazoline (A2M475271,

CA5 476159-98-5).

Inhibitors of histone deacetylase (NAS): (Khatadisny, "). ei aiI., Sapseg 5si., 101(2):355-62 (2010)) voninostat (20Yip7afF); romidepsin (IziodachF); Treicostatin (T5A); oxamflatin; vorinostat (200 mg, suberoylanilide hydroxamic acid); pyroxamide (siberoyl-3-aminopyridinamide hydroxamic acid); Trapoxin (KE-1023A); Trapoxin B (KE-10238); cyclo(α5, 25)-α-amino-p-oxo-2-oxiranoctanoyl-O-methyl-Y-tyrosyl-y -isoleucyl-! - spilled (SuI-1); cycloMaz5, 25)-a- 60 amino-p-oxo-2-oxiranoctanoyl-O-methyl-O-tyrosyl-y -isoleucyl-(25)-2-piperidinecarbonyl|(SuiY-

2Uu; cyclic|-alanyl-O-alanyl-(25)-p-oxo-I-l-aminooxiranoctanoyl-O-prolyl| (HC-toxin); cyclo (a, 25)-a-amino-pd-oxo-2-oxiranoctanoyl-O-phenylalanyl-I-leucyl-(25)-2-piperidinecarbonyl| (M/B-3161); chlamydocin ((5)-cyclic (2-methylalanyl-1 -phenylalanyl-1-prolyl-pd-oxo-1 -x-aminooxiranoctanoyl); apicidin (cyclo(8-oxo-1 -2-aminodecanoyl-1-methoxy-

I -tryptophyll-i -isoleucyl-O-2-piperidinecarbonyl); romidepsin (IziodachF, EV 901228); 4-

Phenylbutyrate; spiruchostatin A; milproin (valproic acid); entinostat (M5 275, M-(2-aminophenyl)-4-(M-(pyridin-3-yl-methoxycarbonyl)-aminomethyl|-benzamide); and depudecin (4,5:8,9- dianhydro-1,2 ,6,7,11-pentadeoxy-O-threo-O-ido-undeca-1,6-dienitol).

Antitumor antibiotics: (Vai, U. ei ai., Seii! Rgoii., 47(3):211-8 (2014)) Doxorubicin (AdgiatusipF and KybrekhF); bleomycin (IepohapefF); daunorubicin (daunorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, SegibidipeF); liposomal daunorubicin (daunorubicin citrate liposome, JuaipoHoteF); Mitoxantrone (ONAYUO, Momapigopef); epirubicin (EPepse"m); idarubicin (IdatusipF, Idatusip REBZF); Mitomycin C (MshiiatusipF); geldanamycin; herbimycin; ravidomycin; and desacetylravidomycin.

Demethylating agents: (Mizsy, T. ei aI., R o5 Ope, (5):610726 (2010)) 5-azacytidine (Midagaf); and decitabine (bTasodepFf)).

Anti-estrogens: (Vpap, A. ei aiYi., / Moi! VioiI., 50022-2836(14)00373-8 (2014)) Tamoxifen (MomaIdekhF); toremifene (RagesiopF); and fulvestrant (RaziodexFf).

Some patients may have allergic reactions to compounds of the present invention and/or other anticancer agent(s) during or after administration; therefore, antiallergic agents are often administered to reduce the risk of an allergic reaction. Suitable antiallergic agents include corticosteroids (Kpiysop, 5., ei al., Rio Ope, 0OI:10.1371LoigpaI.rope.0111840 (2014)), such as dexamethasone (e.g. JuesadopF), beclomethasone (e.g. VesiomepiF), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate and produced under the trademarks AIa-SogpiF, hydrocortisone phosphate, Zoish-SopeiF, Nuagosopy

Aceiated and I apasogif), prednisolone (produced under the trademarks Yuepa-Sope!F,

OgargedF, RediargedF and RegiopefF), prednisone (produced under the trade names

RenazopeF, HydNeifF, MeyisopyepF and OgazopeF), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, manufactured under the trade names YuigayopeF, MeadgyupeF, Meago!F, M-Rgedpizo!Ff and 5oiYi-

Meago!F); antihistamines such as diphenylhydramine (eg, Vepaagu!F), hydroxyzine, and cyproheptadine; and bronchodilators, such as beta-adrenergic receptor agonists, albuterol (eg, RhomepiP) and terbutaline (Vegipep).

Immunomodulators of particular interest for combinations with compounds of the present disclosure include one or more of the following agents: an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule (eg, one or more inhibitors of PO-1, PO-

IT, GAS-3, TIM-3 or STI A4) or any combination of these means.

In some embodiments, the immunomodulator is an activator of a costimulatory molecule. In one embodiment, the agonist costimulatory molecule is selected from an agonist (eg, an agonistic antibody or an antigen-binding fragment thereof or a soluble fusion protein) ligand OX40, 202, С027, СО5, ISAM-1, GEA-1 (СО1ta/С018), ISO5 (00278), 4-188 (C0137), cITV8, CO030, C040, VAREV, NMEM, 207, PSNT, MKO2S, BI AME7, MkKr8vo, CO160, B7-NZ or

SoO83.

In some embodiments, the immunomodulator is an immune checkpoint molecule inhibitor. In one embodiment, the immunomodulator is an inhibitor of PO-1, PO-I1, PO-I2, STI A4,

TIMZ3, GASZ, MI5TA, VTI A, TISIT, GAIKI, СО160, 284 and/or TOEK beta. In one embodiment, the checkpoint immune molecule inhibitor inhibits PO-1, PO-I1, GAS 3, TIM-3, or

STI A4 or any combination thereof. The term "inhibition" or "inhibitor" includes the reduction of a certain parameter, for example, the activity, of a given molecule, for example, an inhibitor of an immune checkpoint molecule. For example, inhibition of activity, for example, activity of PO-1 or

RO-Y1Y at least 5 95, 10 95, 20 95, 30 95, 40 96 or more is covered by this term.

Thus, inhibition does not necessarily have to be 100 95.

Some patients may experience nausea during and after administration of a compound of the present invention and/or other anticancer agent(s); therefore, antiemetics are used to prevent nausea (upper stomach) and vomiting. Suitable antiemetics include aprepitant (EtepaF), ondansetron (2icapF)), granisetron NSI (QuipiF), lorazepam (AimapF), dexamethasone (OesadhopF), prochlorperazine (Sotra?ipeF), casopitant (Ke2opisfF and 7ipgizaf) and combinations thereof.

Treatments to relieve pain during the treatment period are often offered to make the patient more comfortable. Common over-the-counter pain relievers, such as Tuipelf, are often used. However, opioid analgesics such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., Misodip), morphine (e.g., Avigatogrif or Amiplaf), oxycodone (e.g., Ochusopiaf or RegsoseiF), oxymorphone hydrochloride (Orapaf), and fentanyl (e.g., Yugadevzistum) also can be used in case of moderate or severe pain.

To protect normal cells from treatment toxicity and limit organ toxicity, cytoprotective agents (such as neuroprotectors, free radical scavengers, cardioprotectors, anthracycline transudation neutralizers, nutrients, etc.) can be used as adjunctive therapy. Suitable cytoprotective agents include amifostine (Epuo!F)), glutamine, dimesna (TamoseriFf), mesna (MezpehF)), dexrazoxane (7ipesagaeF or ToyesifF), xaliprode (HargiaF) and leucovorin (also known as calcium leucovorin, citrophorum factor and formyltetrahydrofolic acid).

The structure of active compounds, identified by code numbers, universal or trade names, can be taken from the current edition of the standard compendium "Te MegskK Ipdeh" or from databases, for example, Raiepiv Ipiegpaiopa! (for example, IM5 Umogia

Rybiisayopv).

In one embodiment, the present invention relates to pharmaceutical compositions comprising at least one compound of the present invention (e.g., a compound of the present invention) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, suitable for administration to a human or animal, individually or along with other anticancer agents.

In one embodiment, the present invention relates to methods of treating humans or animals suffering from a cellular proliferative disease, such as cancer. The present invention relates to methods of treating a human or animal comprising administering to a patient a therapeutically effective amount of a compound of the present invention (eg, a compound of the present invention) or a pharmaceutically acceptable salt thereof, either individually or in combination with other anticancer agents.

In particular, the compositions are either formulated together in the form of a therapeutic combination or administered

From separately.

In a combination therapy for the treatment of a malignant disease, a compound of the present disclosure and another anticancer agent(s) may be administered simultaneously, in parallel, or sequentially without particular time limitations, such administration providing therapeutically effective levels of both compounds in the patient's body.

In a preferred embodiment, the compound of the present disclosure and the other anticancer agent(s) are typically administered sequentially in any order by infusion or orally.

The mode of administration may vary depending on the stage of the disease, the fitness of the patient, the safety profiles of the individual drugs and the tolerability of the individual drugs, as well as other criteria known to the physician and practitioner(s) administering the combination. A compound of the present invention and another anticancer agent(s) may be administered within minutes, hours, days, or even weeks of each other separately depending on the particular cycle used for treatment. In addition, a cycle may include administration of one drug more often than another during a treatment cycle and at different doses with each drug administration.

In another aspect, the present invention as disclosed herein relates to kits comprising one or more compounds of the present invention and a combination partner. Representative kits include (a) a compound according to the present invention or a pharmaceutically acceptable salt thereof, (B) at least one combination partner, for example, as indicated above, and such kit may include an insert or other labeling, including instructions for administration.

The compound according to the present invention can also be used preferably in combination with known therapeutic methods, for example, the introduction of hormones or especially irradiation. The compound according to the present invention can, in particular, be used as a radiosensitizer, especially for the treatment of tumors showing poor sensitivity to radiation therapy.

In another aspect, the present invention as disclosed herein relates to kits comprising one or more compounds of the present disclosure and a combination partner. Representative kits include (a) a compound according to the present disclosure or a pharmaceutically acceptable salt thereof, (b) at least one combination partner, for example as indicated above, and such kit may include an insert or other labeling, including instructions for administration. 60 In combination therapy according to the invention, a compound according to the present disclosure and another therapeutic agent can be obtained and/or formulated by the same or different manufacturers. In addition, a compound of the present invention and another therapeutic (or pharmaceutical) agent may be combined in a combination therapy: (i) prior to delivery of the combination product to physicians (e.g., in the case of a kit including a compound of the invention and another therapeutic agent ); (iii) by the doctor himself (or under the direction of the doctor) shortly before the introduction; (iii) in the patient himself, for example, during the sequential administration of a compound according to the invention and another therapeutic agent.

Compounds of the present disclosure may also be used as standard or reference compounds, eg, as a quality standard or control, in assays or tests involving EEUO and/or RKS2. Such compounds may be in a commercial kit, for example, for use in a pharmaceutical study involving myeloperoxidase activity. For example, a compound of the present disclosure can be used as a reference compound in a test to compare its known activity with a compound of unknown activity. This would assure the experimenter that the test was performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. In developing new assays or protocols, the compounds of the present disclosure may be used to test their efficacy. Compounds of the present disclosure may also be used in diagnostic tests involving EEO and/or

ASD

A pharmaceutical composition (or composition) for application can be packaged in a number of ways depending on the method used to administer the drug. A conventional product includes a container containing a pharmaceutical compound in a suitable form. Suitable containers are known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, polyethylene bags, metal cylinders, and the like. The container may also include a tamper-proof device to prevent unauthorized access to the contents of the package. In addition, the container has a label describing the contents of the container. The label may also include appropriate warnings.

Claims (26)

FORMULA OF THE INVENTION Zo 1. The compound of Formula (II) (vo i K. F y i M v! vo 7 m-th () or its pharmaceutically acceptable salt, in which: zhi denotes a single bond or a double bond; B' and B2 independently denote H or halogen; BZ is independently selected from: halogen, phenyl and 5-6-ene heteroaryl containing carbon atoms and 1-4 heteroatoms selected from M, MW, O and 5(O)p; and said phenyl and heteroaryl substituted with 0-3 BZA; each BZA is independently selected from: halogen, CM, -(O)t-(Ci-Salkyl, substituted with 0-1 BZB), C--Seghaloalkyl, C:i-Seghaloalkyl, BZ, - О83Э, -0(-0)83О, MAE, -0(-0О)MAZEVZE, - МНО(-О)В8о, -54-0)2839, -5(-0)2MAZEVZE, -MNYAO(-0)2 (C1-Slalkilu) and -SVZOdZEDZO; VZV is independently selected from: OH, MAV Ci-Salalkoxy, -C(-0O)MVeV, -5(-0)2(C:1-Salkylu), - MNOT(-O0)(C1-Salkylu) and 5-6 -membered heterocycloalkyl, which includes carbon atoms and 1-2 heteroatoms selected from M, MA2g, O and 5(O)p; and the indicated heterocycloalkyl is substituted by 0-2 ve; each BZ is independently selected from: C3-Seccycloalkyl, phenyl and a 4-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from M, MAg, O and 5(O)p; and each group is substituted by 0-2 Ve; each HSO is independently selected from: Si-Szalkilu and ZS; BZE and BZE, in each case, independently selected from: H and C/-Szalkilu; each VZ is independently selected from: H and Si-Slalkyl substituted with 0-1 Be; B" is independently selected from: H, halogen, and C:i-Slalkyl; B? is independently selected from: OH and C:-Slalkyl; each Ba is independently selected from: H, -O, C1-Slalkyl substituted with 0-1 Be, -C(-0O)H, -C(2OX(C1-C1-alkyl), -CO5(C1-C1-alkyl), C3-C1-cycloalkyl and benzyl; B? is independently selected from: halogen, OH and C1-C6alkoxy; each Not independently selected of: -O, halogen, OH, C 1 -C 1 alkyl, C 1 -C 1 -haloalkyl, C 1 -C 1 alkyl, and C 1 -C 4 haloalkyl; BZ independently selected from: OH and MAV; B: and NO, in each case, independently selected of: H and Si-Slalkilu; each p independently selected from 0, 1 and 2; and t and n, in each case, independently selected from 0 and 1. 2. The compound or its pharmaceutically acceptable salt according to claim 1, in which: each VZA is independently selected from: halogen, CM, -(O)t-(Si-Slalkyl, substituted 0-1 VZV), C-Sahalogenalkyl, Si-Ca "halogenoxy, VZ, -С(-0)830, MVZEVZE, -С(-О)MAZEVZE, -5(-0)2895, - 5(-О)26MNAZE, -МНО(-О)2(С:- Sialkyl), -"O-C3-Cvcycloalkyl and "im Susalkyl) Be independently selected 3: H, -0, Ci-Salkyl, substituted 0-1 Be, -C(2O)H, -C(2O)(С1 -Salkyl), -bO5(C1-Slalkyl) and C3-Cvcycloalkyl; B" denotes H; t is independently selected from 0 and 1; and n-0. 3. The compound or its pharmaceutically acceptable salt according to claim 1 or claim 2, in which: B' independently denotes H or E; B2 denotes H; and BZ is independently selected from: phenyl and b-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from M and Mag; and the specified phenyl and heteroaryl are substituted by 0-3 VZA, 4. The compound or its pharmaceutically acceptable salt according to any of claims 1-3, in which: Zo VZ is independently selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl; and each group is replaced by 0-3 VZA. 5. The compound or its pharmaceutically acceptable salt according to any one of claims 1-4, in which: Ш ч Я VAZ is independently selected from: 6. The compound or its pharmaceutically acceptable salt according to any of claims 1-4, in which: C sides C we are as. od -x and Ve noYAAh. ZA ZA VZ independently selected from: , (vbo , re and (Kk two. each VZA independently selected from: halogen, CM, -(O)t-(Ci-Slalkyl, substituted 0-1 VZV), C-- Clhaloalkyl, C-Slhalogenalkoxy, -C(-0O)MH";, -C(-0O)MH(C-Slalkyl), --C(-O)M(C1- Slalkyl)", -C(-O)M( C1-Salkylu"CHn)2 M(Si-Slalkyl)", -"СNaМНО(-О)(С1-Slalkyl), -5(-0)2895, - C(-0)2MH(Si-Slalkyl, substituted 0-1 OH), -MNO(-O)2(C1-Salalkyl), MH»g, -MH(C1-Salalkyl), - M(C1-Salalkyl)g, C3-Svcycloalkyl, : ke fr xЯbe с, ayavityu: There is a ticket and 5 and Her" Ha 2 sides and and Czech yaaikinna . Zhov oK tv Zbebzvlki) MU U iy; hee | Her, and and sun; MM Ko: ZAHH c1 ST and ; So soda, da , re , uh gri F lm la M. ml y Z pshrannn nch M | the tire is used to mmm! And ich is 578 and AZV is independently selected from: ОН, МНг, МН(Си-Слалкилу), М(С1и-Слалкилу)», Си-Слаклокси, - Б с(-OM(Си-Слалкилу)», -8( -O)2(Ci-Salkylu), (halogens, I «um M s Z Y Y g ya char M v VK and : BZo independently selected from: C-Slalkyl and 1H-piperidin-4-yl; and each Be independently selected 3: Н, C-Salkylu, -С(2О)Н, -С(2О0)(С1-Сlalkylu) and -СО5(С1-Сlalkylu). 7. The compound or its pharmaceutically acceptable salt according to any one of claims 1-6, in which: 7 B o Y Y Y also VZ independently selected from: he a Kk Ba. each VZA is independently selected from: halogen, CM, -(O)t-(C1-Slalkyl, substituted with 0-1 BZv), C4-Salhaloalkyl, C1-Salhaloalkyloxy, -C(-0O)MH";, -C(- 0О)МН(Si-Slalkyl), --С(-О)М(С1-Slalkyl)", -С(-0)М(С1-Slalkyl)"СНg)»М(С1-Slalkyl)", -" СНаМНО(-О)(С1-С1-Clalkyl), -5(-0)4(С1-С1-Сlalkyl), МНг, МН(С:-С1-С1alkyl), M(С1-С1-С1alkyl)g, С3-Св-cycloalkyl, with A - and pet ish cha gu She ey osa vlyuilivo i i i i le li i V Ko: o plich «im lm mak yi yi | E - Ж | cho ey, ok sebia Ts y 4 sit om che SHE B vo h- ( |, 6 С ж | and it is 2 She a and 2 | V. ke . ve U 1 st s miya mkl shk m M. ; and , chu oo shk: ve. ! Y and i VZV independently selected from: OH, M(C:i-Slalkyl)g, Si--Slalkoxy, "rya M. C : I -C(-O)M(Si-Salkylu)", -8(-0)5(C1-Salkylu), (halogen)ma ve and Fi po te and each Na independently selected from: H, Si-Slalkyl, -C(-O)H, -C(-O)(Si-Slalkyl) and - СОх(С1- Slalkilu). 8. The compound or its pharmaceutically acceptable salt according to any of claims 1-7, in which: each VZA is independently selected from: Е, СИ, СН3, -СН2ОН, СНеЕ, СНЕ», СЕз, СМ, -ОСН», -"OSNeCH 5, - OoCsHn(CHz)", -OSNE", -С0(-0)M(CHz)", -СНаМНО(-О)СНзи, -5(-0)2СНае, МН», cyclopropyl, ; ku ne cha may i osn Z Z 120 t, sh and Zh. 9. The compound or its pharmaceutically acceptable salt according to any of claims 1-8, and the specified compound has the Formula (IA-1): as (A) or a pharmaceutically acceptable salt thereof, wherein: B' is independently H or EC; and VAZA is independently selected from: E, CH3, -CH2OH, CH»E, SNE», CE3 and -OSH». 10. The compound according to claim 1 or claim 2, in which: B' independently denotes H or E; B2 denotes H; BZ denotes independently a 5-membered heteroaryl, which includes carbon atoms and 1-4 heteroatoms selected from М, МН», О and 5(О)р; and the specified heteroaryl is substituted by 0-3 VZA; and Ba is independently selected from: H, C1-C1 alkyl, substituted 0-1 Be, -C(-O)H, -C(5O)(C:-C alkyl), - CO(C1-C alkyl), C3-C8 cycloalkyl and benzyl 11. The compound or its pharmaceutically acceptable salt according to any of claims 1, 2 or 10, in which: and dk Kk lm pesha MMA»: і кх вх "М Z 7» х х и я Su MO and VZ independently selected from: Кк , К , , Sho and 5. SAM uya he 9 sov 12. The compound or its pharmaceutically acceptable salt according to any of claims 1-11, in which: B' denotes EC. 13. The compound or its pharmaceutically acceptable salt according to claim 1, where the specified compound is selected from: 8-(1,3-dimethyl-1H-pyrazol-5-yl)-M-((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)-P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridine -3-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8-(2,4-dimethylpyrimidin-5-yl)-M-((5-fluoro-2,3-dihydrobenzofuran -4-yl)methyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1- isopropyl-3-methyl-1H-pyrazol-4-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl )-8-(b-methoxy-4-methylpyridin-3-yl)-P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine in 8-(6-cyclopropyl-2-methylpyridin-3-yl )-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine (3-(5-((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4)griazolo!|4,3- c|pyrimidin-8-yl)pyridin-2-ylmethanol in 8-(2- cyclopropyl-4-methylpyrimidin-5-yl)-M-((5-fluoro-2,3-dihydrobenz ofuran-4-yl)methyl)-1,2,Agriazoloi/4,3-c|Ipyrimidin-5-amine KI M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8- (2-isopropoxy-4-methylpyrimidin-5-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 3-(5-((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)-((1,2,4)griazolo|4,3-cypyrimidin-8-yl)pyridin-1-oxide M-(2,3-dihydrobenzofuran-4-yl)methyl)-8- (4-((dimethylamino)methyl)phenyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amino M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(4- (methylsulfonyl)phenyl)- P1,2,4Hgriazoloi|4,3-c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-phenyl1,2,4)griazoloi|4 ,3-c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)- 1,2, Aigriazolo!4,3-cIpyrimidin-5-amine 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazolo|4,3-c|Ipyrimidine- 8-yl)-M,M-dimethylbenzenesulfonamide M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-3-yl)-(1,2,4)griazolo|4,3-cypyrimidine - 5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-4-yl)-(1,2,4)griazo 4,3-cyclopyrimidin-5-amino N-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-P1, 2,4Igriazoloi|4,3-s|Ipyrimidin-5-amine M-(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-I(1,2,4|griazoloi| 4,3-c|Ipyrimidin-8-yl)/phenyl)umethanesulfonamide M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(4-methylpiperazin-1-yl)pyridin-3- yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(b-methoxypyridin-3-yl)-P1, 2,Algriazoloi|4,3-c|Ipyrimidin-5-amino 8-(4-(dimethylamino)methyl)phenyl-M-((2-methyl-2,3-dihydrobenzofuran-4-yl)methyl)-P1, 2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amino 8-(4-(dimethylamino)methyl)phenyl-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-P1, 2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidine -5-amino M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1 H-pyrazol-4-yl)-(1,2,4)griazolo|4,3- c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoro-4-(methylsulfonyl)phenyl)-P1,2,4Hygriazoloi|4,3-c| Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-(methylsulfonyl)phenyl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M -(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(methylsulfonyl)pyridin-3-yl)- 2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(piperidin-4-ylsulfonyl)phenyl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(2, 3-dihydrobenzofuran-4-yl)methyl)-8-(1,3-dimethyl-1H-pyrazol-4-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(2 ,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluorophenyl)-P,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 8-(2-chlorophenyl)-M-(2, 3-dihydrobenzofuran-4-yl)methyl-/1,2,4Hygriazolo|4,3-s|Ipyrimidin-5-amine M-(4-(5-((2,3-dihydro 2-(4-(5-((2 ,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Algriazolo|4,3-cyclopyrimidin-8-yl)-1H-pyrazol-1-yl)ethanol M-(2,3-dihydrobenzofuran- 4-yl)methyl)-8-(4-(2-(dimethylamino)ethyl)phenyl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4 -yl)methyl)-8-(5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(methylsulfonyl)phenyl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 2- M-(2-fluoro- 4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4)griazolo|4,3- c|pyrimidin-8-yl)/phenyl) methanesulfonamide 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)-amino)-(1,2,Algriazolo|4,3-cypyrimidin-8-yl)-M-(2-hydroxyethyl)benzenesulfonamide (4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-I(1,2,4|griazolo| 4,3-c|Ipyrimidin-8-yl)/phenyl)(piperazin-1-yl)umethanone 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2, Igriazoloi|4,3-sipyrimidin-8-yl)-M,M-dimethylbenzamide 3-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazolo|4 ,3-c|Ipyrimidin-8-yl)-M,M-dimethylbenzamide M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-3-yl)-(1, 2,4)griazolo|4,3- c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-4-yl)-(1, 2,4Igriazolo|4,3- c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(1-(pyrrolidin-1-yl) ethyl)phenyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoropyridin-3 -yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8-(6-aminopyridin-3-yl)-M-(2,3-dihydrobenzofuran-4-yl)umethyl)-P ,2,Aigriazoli|4,3- c|Ipyrimidin-5-amino 4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Igriazoli|4,3-cIpyrimidine -8-yl)-M,M,2-trimethylbenzamide 8-(4-chloropyridin-3-yl)-M-((2,3-dihydrobenzofuran-4-yl)methyl)-/1,2,Algriazolo| 4,3-s|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrimidin-5-yl)-(1,2,AIgriazolo|4,3-s| Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(b-methylpyridin-3-yl)-P,2,AIgriazoloi|4,3- c|Ipyrimidin-5-amine BZ M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2-(dimethylamino)ethyl)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidine -5-amine BA M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxypyrimidin-5-yl)-I1,2,4Hygriazoloi4,3- c|Ipyrimidin-5-amine BV 4 -(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)amino)-(1,2,4A)griazolo|4,3-c|pyrimidin-8-yl)-M,M -dimethylbenzamide M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(methylsulfonyl)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidine -5-amine 57 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(b-methylpyridin-3-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidine -5-amino BV 8-(6-amino-4-fluoropyridin-3-yl)-M-(2,3-dihydrobenzofuran-4-ylmethyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidine-5 -amine B9 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(3,5-dimethylisoxazol-4-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine in M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyrimidin-5-yl)-1,2,Algryazolo|4,3- pyrimidin-5-amine in M-(2, 3-dihydrobenzofuran-4-yl)methyl)-8-(6-(dimethylamino)pyridin-3Z-yl)-P 1,2,4Hytriazolo|4,3-c|Ipyrimidin-5-amine in 5-(5-((2,3-dihydrobenzofuran-4-yl)umethyl)amino)-(1,2,4Hytriazolo|4,3 -c|Ipyrimidin-8-yl)upicolinonitrile 63 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(b-ethoxypyridin-3-yl)-1,2,4A)triazolo|4,3 - c|Ipyrimidin-5-aminova M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(1,5-dimethyl-1H-pyrazol-4-yl)- P1,2,4Hygriazoloi|4 ,3-s|Ipyrimidin-5-amine 65 8-(6b-cyclopropylpyridin-3-yl)-M-(2,3-dihydrobenzofuran-4-yl)methyl)- P1,2,4Hygriazoli|4,3-s |Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1, 2,4)griazolo|4,3-s|Ipyrimidin-5-amine 67 2-(4-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4) Griazoloyl|4,3-c|pyrimidin-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethanol (5-(5-((2,3-dihydrobenzofuran-4-ylylmethyl)amino )-(1,2,4|griazolo|4,3-c|Ipyrimidin-8-yl)upyridin-2-yl)umorpholino)methanone M-(2,3-dihydrobenzofuran-4-yl)methyl)-8- (b-morpholinopyridin-3-yl)-1,2,4AIgriazolo|4,3-s|Ipyrimidin-5-amine 70 M-(2,3-dihydrobenzofuran an-4-yl)methyl)-8-(5-methyl-6-(methylsulfonyl)pyridin-3-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8-(3, 5-dimethylisoxazol-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 1,2,Algriazoloi4,3-cIpyrimidin-5-amine 72 (4-(5- ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazoloi4,3- c|pyrimidin-8-yl)/uphenyl)(4-methylpiperazin-1- yl)umethanone 73 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-6-morpholinopyridin-3-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin- 5-amine 74 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2,6-dimethylmorpholino)pyridin-3-yl)- P1,2,4Hygriazoli|4,3-s |Ipyrimidin-5-amine 75 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(2-(methylsulfonyl)ethoxy)phenyl)- P1,2,4Hygriazoli|4,3-s |Ipyrimidin-5-amine 76 8-(4-aminopyridin-3-yl)-M-(2,3-dihydrobenzofuran-4-yl)umethyl)-(1,2,4)griazolo|4,3- c| Ipyrimidin-5-amine 77 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(piperazin-1-yl)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3 -c|Ipyrimidin-5-amine 78 8-(6-(difluoromethoxy)pyridin-3-yl)-M-(2,3-dihydrobenzofur an-4-yl)methyl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amino 5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1 ,2,)griazolo|4,3-c|Ipyrimidin-8-yl)-M-methylpicolinamide (5-(5-((2,3-dihydrobenzofuran-4-ylmethyl)amino)-(1,2,4| griazoloi|4,3-c|Ipyrimidin-8-yl)upyridin-2-yl)(pyrrolidin-1-yl)umethanone Vi M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(b- thiomorpholinopyridin-3-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidine-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)- 5-amino M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(methoxymethyl)-5-methylpyridin-3-yl)- P1,2,4Hygriazoli|4,3-c|Ipyrimidine -5-amino 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Algriazolo|4,3-cypyrimidin-8-yl)upyridin-2- yl)ethanol M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoropyridin-3-yl)-(1,2,4|triazolo|4,3- c|Ipyrimidin-5- amine vv M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2-methoxyethyl)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5 -amino 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Algriazolo|4,3-cypyrimidin-8-yl)upyridin-3-yl) pyrrolidin-2-one M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(dimethylamino)pyrimidin-5-yl)- 5-amine in M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-(2-(dimethylamino)ethyl)phenyl)-1,2,Algriazolo4,3-sipyrimidin-5-amine in M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4,4-dimethyl-4,5-dihydrooxazol-o-yl) upyridin-3-yl)-(1,2,4|)triazolo|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8- (b-thiomorpholinopyridin-3-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-( b-morpholinopyridin-3-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amino 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino )-I(1,2,4)triazolo|4,3-c|pyrimidin-8-yl)picolinonitrile M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2- fluorophenyl)-(/1,2,4)griazolo|4,3- c|Ipyrimidin-5-amino 5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2 ,)griazolo|4,3-sipyrimidin-8-yl)-M,M-dimethylpicolinamide SYA M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2-methylpyrrolidin-1-yl) )pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amino methyl-4-(5-(5-((2,3-dihydrobenzofuran-4-yl)umethyl)amino )-1,2,4Hygriazoloi|4,3- c|Ipyrimidin-8-yl)pyridin-2-yl)piperazine-1-carboxylate SYA M-(2,3-dihydrobenzofuran-4-yl)methyl)-8- (5-(3-"methylsulfonyl)propoxy)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine in 99 2-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Algriazolo|4,3-cypyrimidin-8-yl)upyridin-2-yl) upropan-2-ol 8-(6-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)-M-((2,3-dihydrobenzofuran-4-yl)methyl)- 1,2,Agriazoloi/4,3-c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(4,4-dimethyl-4,5-dihydrooxazole) -o-yl)upyridin-3-yl)-(1,2,4|)triazolo|4,3-c|Ipyrimidin-5-amine 5-(5-((2,3-dihydrobenzofuran-4-yl) methyl)amino)-(1,2,)griazolo|4,3-c|Ipyrimidin-8-yl)-M- 2-(dimethylamino)ethyl)-M-methylpicolinamide M-(2,3-dihydrobenzofuran-4- yl)methyl)-8-(5-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)-P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine 4-(5- 4- (5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Al-triazoloyl|4,3-cypyrimidin-8-yl)-3-methylpyridin-2-yl)piperazine -2-one M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2-(methylsulfonyl)ethoxy)pyridin-3-yl)- P1,2,4Hygriazoli|4,3- with|Ipyrim Idin-5-amino 4-(2-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Algriazolo|4,3-c|Ipyrimidine-8- yl)pyridin-2-yl)ethyl)piperazine-1-carbaldehyde 1-(4-(2-(5-(5-((2,3-dihydrobenzofuran-4-yl)-methyl)amino)-/1, 2,4|htriazolo|4,3- c|pyrimidin-8-yl)pyridin-2-yl)uethyl)piperazin-1-yl)ethanol 4-(2-(5-(5-((2,3- 2-(4-(5 -(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,Algriazolo|4,3-c|Ipyrimidin-8-yl)upyridin-2-yl)piperazin-1- il)ethanol 144 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoro-6-(methylamino)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin- 5-amino 112 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(dimethylamino)-4-fluoropyridin-3Z-yl)-P1,2,4Hygriazoloi|4,3-s| Ipyrimidin-5-amino 113 4-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4)griazolo|4,3-s|pyrimidine-8- yl)pyridin-2-yl)-1,4-diazepan-1-carbaldehyde 114 5-(5-((2,3-dihydrobenzofuran-4-yl)umethyl)amino)-(1,2,4Altriazolo|4, 3-s|Ipyrimidin-8-yl)-M-ethylpicolinamide 115 M-(5-fluoro-2,3-dihydrobenzofuran-4-ylmethyl)-8-(h-fluoropyridin-3-yl)-1,2,4 )griazolo|4,3-c|Ipyrimidin-5-amine 116 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-4-yl)-P1,2 ,4Griazoli|4,3-c|Ipyrimidin-5-amine 117 3-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4)griazoli|4 ,3-c|Ipyrimidin-8-yl)upyridin-2-yl)uoxazolidin-2-one M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methylpyridin-3 -yl)- 1,2,Algriazoloi4,3-cyclopyrimidin-5-amine 119 8-(6b-cyclopropylpyridin-3-yl)-M-((5-f thor-2,3-dihydrobenzofuran-4-yl)methyl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 120 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl) umethyl)-8-(2-morpholinopyridin-4-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 124 2-(5-((5-fluoro-2,3-dihydrobenzofuran- 4-yl)umethyl)amino)-(1,2,4A)griazolo|4,3-c|pyrimidin-8-yl)benzonitrile 122 2-(5-((5-fluoro-2,3-dihydrobenzofuran-4 -yl)umethyl)amino)-(1,2,4A)griazolo|4,3-c|pyrimidin-8-yl)benzamide 123 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-( 2-methylpyridin-3-yl)-P1,2,Agriazoloi|4,3- s|Ipyrimidin-5-amine 8-(4-chloropyridin-3-yl)-M-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)- 124. : - P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 125 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino)-I(1,2 ,4)griazolo|4,3-c|Ipyrimidin-8-yl)upiridin-2-yl)piperazin-2-one 126 1-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl) )amino)-I(1,2,4)griazolo|4,3-c|Ipyrimidin-8-yl)upyridin-2-yl)azetidin-3-ol 127 M-(5-fluoro-2,3Z-dihydrobenzofuran -4-yl)methyl)-8-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-1,2,4Zgriazolo|4,3-c|Ipyrimidin-5-amine 128 M-(5- fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)-1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine ( 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|triazolo|4,3- cIpyrimidin-8-yl)pyridin-2-yl )(pyrrolidin-1-yl)umethanone 130 (5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazoloi4,3- c| Pyrimidin-8-yl)-4-methylpyridin-2-yl)(pyrrolidin-1-yl-methanone 134 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- (1,2,4|griazolo|4,3-c|pyrimidin-8-yl)-M,M,4-trimethylpicolinamide 132 M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)meth l)-8-(1,3,5-trimethyl-! N-pyrazol-4-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 133 4-(5-(5-((2,3-dihydrobenzofuran-4-yl)methyl)amino )-(1,2,4Itriazolo|4,3-c|Ipyrimidin-8-yl)upyridin-2-yl)umethyl)piperazin-2-one 134 4-(5-(5-((2,3-dihydrobenzofuran -4-yl)methyl)amino)-(1,2,Agriazolo|4,3-c|Ipyrimidin-8-yl)pyridin-2-yl)piperazine-1-carbaldehyde 135 3-(5-(5-( (2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4)griazolo|4,3-s|Ipyrimidin-8-yl)upyridin-2-yl)-M,M-dimethylpropanamide 136 M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-8-(4-(trifluoromethyl)pyridin-3-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidine-5 -amine 137 M-(2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(methoxymethyl)-6-methylpyridin-3-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidine -5-amino 138 8-(4-chloro-6-methoxypyridin-3-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-ylmethyl)- P1,2,4Hygriazoli|4,3- c|Ipyrimidin-5-amine 139 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-6-(methylsulfonyl)pyridin-Z-yl)-1,2 ,4Zgriazolo|4,3-s|Ipyrimidine-5-amine 140 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-11,2,4|griazolo|4,3-c|pyrimidin-8-yl)-M, M-dimethylpicolinamide M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxypyridin-Z-yl)-141. and : P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(b-methoxypyridin-Z-yl) - 142. and : 1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine 8-(1-ethyl-1H-pyrazol-5-yl)-M-((5-fluoro-2,3-dihydrobenzofuran -4-yl)umethyl)- 143 : : I P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8 -(1-isopropyl-1H-pyrazol-5-yl)- 144 : : : P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran- 4-yl)methyl)-8-(2-methoxypyridin-4-yl)- 145 : : : P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 146 8-(2,4-dichlorophenyl) -M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-(1,2,4A|griazolo|4,3- c|Ipyrimidin-5-amine 147 M-(5-fluoro-2 ,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-4-yl)-1,2,Al-triazoloyl4,3-cyclopyrimidin-5-amine M-(5-fluoro-2 ,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3-(trifluoromethyl)-1H-148 : : . . x pyrazol-4-yl)-(1,2,4)griazoloi|4 ,3-c|pyrimidin-5-amine 8-(1-cyclopropyl-1H-pyrazol-4-yl)-M-(2,3-dihydrobenzofuran-4-yl)umethyl)- 149 : : : P1,2 ,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 8-(1-cyclopropyl-1H-pyrazol-4-yl)-M-((5-fluoro-2,3Z-dihydrobenzofuran-4-y l) umethyl) - 150 and . . P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3,5-dimethyl- 1 H-pyrazol-151: ... 4-yl)-1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine 152 M-(2,3-dihydrobenzofuran-4-yl)methyl) -8-(1-methyl-1H-pyrazol-5-yl)-(1,2,4)griazolo|4,3- c|Ipyrimidin-5-amine M-(2,3-dihydrobenzofuran-4-yl) )methyl)-8-(1-isopropyl-3,5-dimethyl-!H-pyrazol-4-yl)-153 2 . . P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8-(6-(difluoromethyl)pyridin-3-yl)-M-((2,3-dihydrobenzofuran-4-yl)methyl)- 154 . . A P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,Z-dihydrobenzofuran-4-yl)methyl)-8-(b-methoxy-2-methylpyridine-Z -yl)- 155 and i: P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 8-(6-amino-2-methylpyridin-3-yl)-M-(5-fluoro-2, 3-dihydrobenzofuran-4-yl)methyl)- 156 and . ; P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 4 8-(2-chloro-4-fluorophenyl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)- 57. y : P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 2-(4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)-methyl)amino)-P1 ,2,4Hygriazoloi|4,3- pyrimidin-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethanol 159 M-(5-fluoro-2,3-dihydrobenzofuran-4-yl) methyl)-8-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-(1,2,4)griazolo|4,3-c|pyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-«(trifluoromethyl)pyridin-3-yl)- 160 and i : P1,2,4Hygriazoli|4,3- c|Ipyrimidin-5-amine 161 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)umethyl)-8-(4-fluoro-b-methoxypyridin-3Z-yl)-P1,2,4Hriazoloi| 4,3-s|Ipyrimidin-5-amine 8-(3-chloropyridin-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 162 . : - P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 163 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(Z-methylpyridin-4-yl) )- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-8-(6-fluoro-2-methylpyridin- 3-il)- 164 . and : P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 165 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)umethyl)-8-(4-fluoro-2-methylphenyl) )- P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-8-(2-(trifluoromethyl)pyridine-3 -yl)- 166 and i : P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 8-(2,6-dimethylpyridin-3-yl)-M-((5-fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)- 167. ; - P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine 8-(2-(difluoromethyl)pyridin-3-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl) )umethyl)- 168 . . A P1,2,4Hygriazoles|4,3-s|Ipyrimidine-5-amine M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-5-yl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidine -5-amine M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-(1, 2,4)griazolo|4,3-c|pyrimidin-5-amine M-((5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-I(1 . 2,3-dihydrobenzofuran-4-yl)methyl)-P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine 8-(6-cyclopropyl-4-methylpyridin-3-yl)-M-(( 5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl) )methyl)-8-(2-methoxypyrimidin-5-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl) methyl)-8-(2-methoxy-4-methylpyrimidin-5-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4 -yl)methyl)-8-(4-methylpyrimidin-5-yl)-1,2,Algriazolo4,3-sipyrimidin-5-amine 8-(2,3-dimethylpyridin-4-yl)-M-((5 -fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 4-(5-((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)-((1,2,4)griazolo|4,3-pyrimidin-8-yl)-3-methylbenzonitrile 8-(1-cyclopropyl-3,5-dimethyl-1H-pyrazole -4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-(1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine M-( 5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoro-3-methylpyridin-4-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8-(2-(difluoromethyl)-3-methylpyridin-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-(1,2,4)griazolo|4, 3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2-(fluoromethyl)-3-methylpyridin-4-yl)-P1,2 ,4Igriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoro-5-methylpyridin-4-yl)- P1,2,4Hygriazoles|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-2-(trifluoromethyl)pyridine -4-yl)-1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2 -(trifluoromethyl)pyridin-4-yl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine (28)-1-(4-(5-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)-11,2,4)griazolo|4,3- c|pyrimidin-8-yl)-3,5-dimethyl-1H-pyrazol-1-ylpropan-2-ol (25)-1-(4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4)griazolo|4,3- cIpyrimidine-8- yl)-3,5-dimethyl-1H-pyrazol-1-yl)upropan-2-ol M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl -5-methyl-1H-pyrazol-4-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 2-(4-(5-((5-fluoro-2,3- 2-( 4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)amino)-/1,2,4)griazolo|4,3- c|pyrimidin-8-yl)-3- methyl-1H-pyrazol-1-yl)ethanol 8-(4-(difluoromethyl)pyrimidin-5-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1, 2,4)griazolo|4,3-c|Ipyrimidin-5-amine 8-(1-cyclopropyl-1H-pyrazol-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl) methyl)- P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine M-(5-phto p-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(2-(fluoromethyl)pyridin-3-yl)-P1,2,4Hgryazolo(4,3-c|Ipyrimidin-5-amine 8-( 2,5-dimethylpyridin-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8 -(1,3-dimethyl-1H-pyrazol-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- P1,2,4Hygriazoloi|4,3-c| Ipyrimidin-5-amine 8-(6-ethoxy-4-methylpyridin-3-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-P1,2,4Hygriazoli|4,3 -c|Ipyrimidin-5-amine 8-(6-(difluoromethoxy)-4-methylpyridin-3-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-(1, 2,4)griazolo|4,3-s|Ipyrimidine-5-amine 198 8-(2-(difluoromethyl)-5-methylpyridin-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-(1,2,4)griazoli|4 ,3-c|Ipyrimidin-5-amine 199 5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazoloi|4,3- c|pyrimidin-8-yl)-M,M,6b-trimethylpicolinamide 8-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-M-(5-fluoro-2,3- dihydrobenzofuran-4-200 |. . . . yl) umethyl)-(1,2,4)griazolo|4,3-s|Ipyrimidin-5-amine 8-(2-(difluoromethyl)-6-methylpyridin-3- yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4- 201 and I: - yl)umethyl)-(1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine 202 M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridazin-4-yl)-(1,2,4|griazolo4,3- c|Ipyrimidin-5-amine M- (5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-7-methyl-8-(2-methylpyridin-Z-yl)- 203 i i : P1,2,4Hygriazoloi|4,3-c| Ipyrimidin-5-amino 204 3-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)-methyl)amino)-(1,2,4|griazoloi4,3- c|pyrimidine-8- yl)-2-methylpyridin-1-oxide M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(pyrazin-2-yl)-1,2,4AIgriazolo|4,3- Cypyrimide in-5-amine 206 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(pyrimidin-5-yl)-P1,2,AIgriazoloi|4,3- c|Ipyrimidin- 5-amine 207 M-(5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-1,2,4triazolo|4,3- c|Ipyrimidin-5-amine 208 M- (benzofuran-4-ylmethyl)-8-(4-((dimethylamino)methyl)phenyl)-(1,2,4)griazolo|4,3- c|Ipyrimidin-5-amine 209 M-(benzofuran-4- ylmethyl)-8-(4-(4-methylpiperazin-1-yl)uphenyl)-P1,2,4|griazolo|4,3- c|Ipyrimidin-5-amine 210 M-(benzofuran-4-ylmethyl)- 8-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)-(1,2,4)griazolo|4,3- c|Ipyrimidin-5-amine 214 M-(benzofuran-4-ylmethyl) -8-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-P1,2,Agriazoloi|4,3- c|Ipyrimidin-5-amine 212 M-(benzofuran-4-ylmethyl)- 8-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-P1,2,Agriazoloi|4,3- c|Ipyrimidin-5-amine M-(benzofuran-4-ylmethyl)-8- (pyridin-3-yl)-(1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 214 M-(benzofuran-4-ylmethyl)-8-(4-(methylsulfonyl)phenyl)-P1, 2,4|triazolo|4,3- s|Ipyrimidin-5-amine 215 M-(benzofuran-4-ylmethyl)-8-(4-(isopropylsulf onyl)phenyl)-(1,2,4|griazoly|4,3- c|Ipyrimidin-5-amine 216 (4-(5-(benzofuran-4-ylmethyl)amino-(1,2,4|griazoly| 4,3-c|Ipyrimidin-8-yl)/uphenyl)(pyrrolidin-1-yl)umethanone M-(benzofuran-4-ylmethyl)-8-phenyl-(1,2,4|Hygriazolo|4,3- c|Ipyrimidin-5-amine M-(benzofuran-4-ylmethyl)-8-(pyridin-4-yl)-(1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 8-(4- (dimethylamino)methyl)phenyl)-M-(5-fluorobenzofuran-4-yl)methyl)- 219 in ; . P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine M-(benzofuran-4-ylmethyl)-8-(4-(1-methylpiperidin-4-yl)usulfonyl)phenyl)- 220 . . - P1,2,4Hygriazolo|4,3-c|Ipyrimidin-5-amine 224 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(pyrimidin-5-yl)-P1 ,2,Algriazoloi|4,3- c|Ipyrimidin-5-amine 8-(4,6-dimethylpyridin-3-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl) - 222. ; - P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amino 8-(6-(dimethylamino)methyl)-2-methylpyridin-3-yl)-M-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)-1,2,Agriazoloi/4,3-c|Ipyrimidin-5-amine 8-(6b-ethyl-4-methylpyridin-3-yl)-M-((5-fluoro- 2,3-dihydrobenzofuran-4-yl)methyl)- 224 : : . P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 22 8-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4- |. . . . yl)umethyl)-(1,2,4)griazolo|4,3-c|Ipyrimidin-5-amine 8-(2-ethoxy-4-methylpyrimidin-5-yl)-M-((5-fluoro-2 ,3-dihydrobenzofuran-4-yl)umethyl)- 226 : : . P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 227 (4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2, 4|griazolo4,3-c|pyrimidin-8-yl)-1-methyl-1H-pyrazol-5-yl)umethanol 228 8-(2-chloro-5-methylpyridin-4-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-ylmethyl)- P1,2,4Hygriazoloi|4,3-c|Ipyrimidine- 5-amine 229 8-(6b-ethyl-2-methylpyridin-3-yl)-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- P1,2,4Hygriazoli|4,3 -c|Ipyrimidin-5-amine 230 M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)umethyl)-8-(2-methoxy-3-methylpyridin-4-yl)-P1,2,4Hygriazol |4,3-c|Ipyrimidin-5-amine 234 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-2-yl)-P1,2,4Hygriazoloi4,3 - c|Ipyrimidin-5-amine 232 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(5-methylpyridin-3-yl)-P1,2,4Hygriazoli|4,3 -c|Ipyrimidin-5-amine 233 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-P1,2, 4Griazoloi|4,3-c|Ipyrimidin-5-amine 234 (5-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-(1,2,4|griazoloi4, 3- c|pyrimidin-8-yl)pyridin-2-ylmethanol 8-fluoro-M-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-P,2,4Hygriazolo|4,3- c|Ipyrimidin-5-amine 236 8-(2,4-dimethyl-1H-imidazol-1-yl)-M-(5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 237 M-(5-fluoro-2,3Z-dihydrobenzofuran-4-yl)methyl)-8-(1 H -pyrazol-1-yl)-1,2,4|griazoloi4,3- c|Ipyrimidin-5-amine 238 M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3 -methyl-1H-1,2,4-triazol-1-yl)-P1,2,4Hygriazoloi|4,3-s|Ipyrimidin-5-amine 239 M-(5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)-8-(4-methyl-1H-pyrazol-1-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 240 M-(5-fluoro-2 ,3Z-dihydrobenzofuran-4-yl)methyl)-8-(1H-imidazol-1-yl)-(1,2,Algriazolo|4,3- c|Ipyrimidin-5-amine 244 M-(5-fluoro- 2,3-Dihydrobenzofuran-4-yl)methyl)-8-(1H-1,2,4-triazol-1-yl)-P1,2,4Hygriazoloi|4,3-c|Ipyrimidin-5-amine 242 B-fluoro-4-((8-(2-methylpyridin-3-yl)-P1,2,4)griazolo|4,3-c|Ipyrimidin-5-yl)amino)methyl)- 2,3-dihydrobenzofuran -3-ol 243 B-fluoro-4-((8-(2-(hydroxymethyl)pyridin-3-yl)-(1,2,4|triazolo|4,3-c|pyrimidin-5-ylluamino)methyl )-2,3-dihydrobenzofuran-3-ol 244 3-(5-((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-yl)umethyl)amino)-(1,2,4A)griazol |4,3- s|pyrimidine-8- yl)-2-methylpyridin-1-oxide 245 8-(1,2-dimethyl-1H-imidazol-5-yl)-M-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-P1 ,2,4Hygriazolo|4,3-s|Ipyrimidine-5-amine 14. The compound according to claim 1, where the specified compound is selected from: E e N M. OM M M There is more | o still I M M z / z / khi ly I We M M schi M E y NN M M M M M M: o a o in M ee ZM Ii 7 r y y -8-O M - M- M M z with E ER Nn N M M M. M | 5 (9); ve o M MO and M | X / Y; 24 t-m - 2 M-M M o m and its pharmaceutically acceptable salt. 15. The compound according to claim 1, where the specified compound is IS M. MN o o i ho Y MM М-M or its pharmaceutically acceptable salt. 16. The compound according to claim 1 or its pharmaceutically acceptable salt, where the specified compound is IS M. OM V y i oh 7 r h- M M I 17. The compound according to claim 1 or its pharmaceutically acceptable salt, where the specified compound is E. ma y vo, x I (17 M m y 18. The compound according to claim 1 or its pharmaceutically acceptable salt, where the specified compound is IS. the city of Mvav; M steering wheel aa; In M-M 19. The compound according to claim 1 or its pharmaceutically acceptable salt, where the specified compound is IS. m. y GO o M ye5 FV; oh M 20. The compound according to claim 1 or its pharmaceutically acceptable salt, where the specified compound is E N M M a r Ma 7 zu M 21. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound or its pharmaceutically acceptable salt according to any one of claims 1-20. 22. Pharmaceutical composition according to claim 21, which additionally includes at least one additional therapeutic agent. 23. Pharmaceutical composition according to claim 22, in which at least one additional therapeutic agent is selected from other anticancer agents, immunomodulators, antiallergic agents, antiemetics, analgesics, cytoprotective agents, and combinations thereof. 24. The compound or its pharmaceutically acceptable salt according to any one of claims 1-20 for use in therapy. 25. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20 for the preparation of a medicinal product for the treatment of a disease or disorder mediated by EEO and/or ASD. 26. The use of claim 25, wherein said disease or disorder is selected from diffuse large B-cell lymphoma, follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rod-shaped tumor, hepatocellular cancer, prostate cancer, cancer breast cancer, bile duct and gallbladder cancer, bladder cancer, brain tumors including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell cancer, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas. 0 Computer keyboard. Matselo 00000000 777 Ministry of Economic Development, Trade and Agriculture of Ukraine, (0000000 12/2 M. Hrushevsky St., Kyiv, 01008, Ukraine SE "Ukrainian Institute of Intellectual Property", 1 Glazunova St., Kyiv - 42, 01601